A Comparative Randomized Clinical Study Assessing the Efficacy of a 1% Selenium Disulfide-Based Shampoo versus 2% Ketoconazole Shampoo in Subjects with Moderate to Severe Scalp Seborrheic Dermatitis

Seborrheic dermatitis (SD) is a chronic and relapsing inflammatory skin condition of sebum-rich areas, including the scalp, face, and chest. Scalp seborrheic dermatitis (SSD) may cause erythema and scaling, resulting in greasy and flaky scalp, as well as itching [1]. Its prevalence in the adult population is estimated at up to 5% [2, 3].

Environmental, intrinsic, and host immune factors may contribute to the development of SD. These factors may trigger a modification of the sebaceous gland activity and sebum composition, an epidermal barrier dysfunction, and skin surface fungal colonization, which ultimately leads to inflammation. Malassezia spp. metabolizes and oxidizes sebum-derived lipids such as triglycerides, squalene, and fatty acids into inflammatory compounds, thus producing indole derivatives (malassezin, indolocarbazole) and, in parallel, its activity against aryl hydrocarbon receptors triggers skin inflammation [4, 5]. M. restricta is particularly associated with SD [6]. This causes cytotoxicity to keratinocytes in vitro, thereby suggesting an active role in the accelerated flake formation [7].

Current SSD treatments consist of topical antifungal and anti-inflammatory agents [8]. Ketoconazole is a fungistatic agent that limits Malassezia restricta, M. globosa and M. furfur growth [9]. In vivo, the clinical efficacy of 1% to 2% ketoconazole resulted in lower loads of Malassezia spp. thus supporting the contribution of these fungi in the physiopathology of SD [10, 11]. When ketoconazole is interrupted, the signs and symptoms of SD relapse [10, 12].

1% selenium disulfide (SeS₂)-based shampoo (Dercos^® anti-dandruff DS, Vichy Laboratoires, France) is another effective means in the treatment of dandruff, a milder form of seborrheic dermatitis [13]. SeS₂ has antifungal properties against Malassezia spp and also inhibits Staphylococcus epidermidis in vitro. It restores the natural equilibrium of the scalp microbiota after 28 days of use by modifying the global bacterial distribution. The Staphylococci load is decreased in favor of a higher Cutibacterium load level [9, 14]. Past reports on SSD/dandruff treatment have focused on Malassezia spp and its population counts, but the specific microbiota changes have been poorly described [15, 16]. Additionally, the SeS₂ shampoo contains 1.0% salicylic acid, known for its keratolytic activity, that reduces the scalp scales [8, 17].

Recent studies confirmed the clinical benefit of SeS₂ shampoo in dandruff and SSD, as well as a maintenance therapy after initial treatment with topical corticosteroid/salicylic acid and ketoconazole [18‒21]. The objective of our study was to compare the clinical benefit of 1% SeS₂ shampoo versus an commercially available 2% ketoconazole shampoo (NIZORAL^® 20 mg/g shampooing, Janssen Pharmaceutica NV, Belgium) in subjects with moderate to severe SSD.

This was a multi-centre, double-blind, randomized clinical study. The study was conducted at two investigational sites in Mauritius and Brazil. The study complied with legal local regulations, good clinical practices, and the principles of the Declaration of Helsinki. All subjects provided written informed consent prior to inclusion.

Suitable subjects were to be between 18 and 64 years of age, of any race and phototype, and have clinically confirmed moderate to severe SSD (SSSD score >6 on a scale from 0 = none to 15 = very severe, comprising two subscores ranging each from 0 = none to 5 = very severe for erythema and scales, and a visual analog scale ranging from 0 mm = none to 100 mm = very severe itching) at baseline. A minimum of 2 weeks wash-out period was required prior to the start of the clinical trial.

Subjects were randomized to receive either SeS₂ shampoo 3 times per week or ketoconazole shampoo 2 times per week according to the respective indications for use for 28 days. Both products were provided by the investigator to the participants. No hair care products (i.e., conditioner, hair mask, non-rinsed hair care product, oil, etc.) other than the tested products were allowed during the study.

At all visits, and in addition to the SSSD, the investigator assessed at baseline, Day (D) 3, 7, 14, and 28, the severity of total scales (TSS, sum of adherent, and non-adherent scales, from 0 = no scales to 5 = a very large quantity of scales), the severity of erythema, as well as that of hair and scalp seborrhea (all from 0 = none to 5 = severe); global irritation was assessed at all visits (scale from 0 = none to 4 = severe). At D28, the investigator also rated the global product satisfaction (0 = not satisfied to 2 = very satisfied) and global efficacy on a scale from 1 = worse to 5 = complete resolution or complete remission.

The subject rated the severity of itching and the product efficacy (scales and greasy aspect) on a scale from 0 = not at all to 9 = hugely and their product satisfaction (cosmeticity, acceptability, global satisfaction, and efficacy) at all visits. QoL was assessed at all visits using the SCALPDEX questionnaire [22].

Local tolerance was assessed by the investigator for each subject (from very well tolerated to not well tolerated) at all visits. For each subject, the % change was computed. The % change of each treatment group at timepoint t was the arithmetic mean of the percentages.

For QoL, the percentage change of each treatment group at timepoint t (after baseline, D0) was calculated on the mean value observed for each parameter, as described in the formula. For the tolerance evaluation, the number of subjects reporting each sign was summarized in a frequency table at each timepoint. For each parameter and timepoint, the evolution across time with respect to the baseline for each treatment group was investigated using the Student’s paired t test.

An analysis of covariance was performed at each post-baseline timepoint on changes with respect to baseline with “treatment” as fixed factor and “baseline values” as covariate. The difference of the least square means between SeS₂ and Ketoconazole shampoo was given with its 95% CI and associated p value, followed by a Dunnett adjustment for multiple comparisons.

For parameters where no baseline values were available, the analysis was conducted on the values observed at the specific timepoints and not on the difference data. In cases of deviation from normality, tested at 1% level of the Shapiro-Wilk test on the standardized residuals produced by the model for treatment comparison, or on the difference data for pairwise comparisons between two timepoints, the non-parametric alternative was considered to check for the sensitivity of the results.

A p value less or equal to 0.05 was considered for statistical significance. The statistical analysis was performed using Microsoft Excel (Office 365), IBM SPSS version 19.0 and SAS version 9.4.

In total, 64 subjects were included in the study, 35 subjects received SeS₂ and 29 ketoconazole shampoo. The overall mean age was 34 years, 91% were female. Subjects with phototypes from II to VI were included.

At baseline, 74.3% in the SeS₂ and 72.4% in the ketoconazole shampoo group had an SSSD score of 7–9, corresponding to moderate SSD. The remaining subjects had severe SSD. The mean TSS for SeS₂ and ketoconazole shampoo were 5.8 ± 1.41 and 5.65 ± 1.18, respectively.

Table 1 presents the demographic data and Table 2 the baseline conditions. The SSD score significantly improved in both groups as early as D3 after the first application of shampoo (p < 0.001). The decrease was −71% for SeS₂ and −69% for ketoconazole at D28. By the end of the study, the severity score changed for all subjects from moderate or severe to mild. The evolution of the mean scores over time is given in Figure 1.

The mean score of non-adherent and adherent scales significantly (p < 0.001) decreased in both groups starting at D3. Results at D28 showed a mean decrease of non-adherent scales with SeS₂ shampoo of −75.5% and with ketoconazole of −67.5%, while adherent scales decreased by 73.5% and 67.3% with SeS₂ and ketoconazole shampoo respectively. In both groups, the TSS significantly (p < 0.001) decreased (−75.0% for SeS₂ and −68.0% for ketoconazole shampoo) at D28 (Fig. 2).

The global irritation score significantly (p < 0.001) decreased with SeS₂ by 66.0 ± 41.6% and with ketoconazole shampoo by −60.3 ± 27.3% after 28 days as early as D3 (both p ≤ 0.05). So did erythema with SeS₂ (−63.9 ± 40.9%) and ketoconazole shampoo (72.3 ± 50.8%), and itching (SeS₂ shampoo: −67.8 ± 35.0% and ketoconazole: 47.1 ± 46.5%). Greasiness assessed by the investigator significantly (p ≤ 0.044) improved with SeS₂ shampoo starting at D7, compared to ketoconazole shampoo, which showed a significant (p < 0.011) improvement at D28 only. Again, no significant difference between groups was observed for any sign or symptom. Detailed results for improvement can be seen in Figure 3.

Figure 4 provides visual support for the improvement of clinical signs in subjects having received SeS₂ shampoo for 28 days. Between-group differences were statistically insignificant for any parameter and at any visit.

The blinded investigators rated both shampoos as equally efficacious for the treatment of SSD, with mean scores of 4.3 ± 0.6 and 4.2 ± 0.5 for SeS₂ and ketoconazole shampoo, respectively, after 28 days of use and corresponding to an important improvement. Globally, investigators were highly satisfied with both shampoos (1.7 ± 0.5 and 1.5 ± 0.5 for SeS₂ and ketoconazole shampoo, respectively).

Efficacy assessed by the subjects was considered similar for both shampoos. Both shampoos significantly (p ≤ 0.03) improved scales, at all post-baseline visits.

QoL significantly (p < 0.001) improved for all items (emotions, functions, and symptoms), as reflected in the decrease of the global SCALPDEX scores for both SeS₂ shampoo (29.1 ± 19.0 at D28 vs. 52.11 ± 23.66 at baseline) and ketoconazole (23.7 ± 19.7 vs. 41.0 ± 25.3 at the same time points) after 28 days. A significantly (p = 0.031) quicker onset of the improvement of emotions compared to ketoconazole shampoo was observed at D7. See Figure 5 for detailed results.

Cosmetic acceptability of SeS₂ shampoo was higher than ketoconazole. Overall, 82.0% of the subjects who applied SeS₂ shampoo stated that their hair was soft and glossy compared to 62.0% and 69.0%, respectively, with ketoconazole shampoo, 74.0% stated that SeS₂ shampoo gave their hair volume (ketoconazole shampoo: 52%), 68.0% stated that SeS₂ shampoo left their hair easy to disentangle (ketoconazole: 55.0%) and 91.0% (79.0% in the ketoconazole group) stated that their scalp seemed to be less sensitive. All subjects (100%) in the SeS₂ and 93.1% in the ketoconazole shampoo group were satisfied with their shampoo; 97% stated to be willing to continue the use of SeS₂ shampoo. Both products were safe and very well tolerated.

This is the first study to compare the use of SeS₂ shampoo versus ketoconazole in subjects with moderate to severe SSD, in a randomized, double-blinded design. The study showed that SeS₂ shampoo is as beneficial as the pharmacologically active treatment of 2% ketoconazole in managing SSD and is very well tolerated.

The SSD severity, total number of scales, as well as clinical signs and symptoms significantly (all p < 0.05) and equally improved as early as after 3 days of use of SeS₂ shampoo or of 2% ketoconazole shampoo, with a maintained benefit up to 28 days, and a faster onset of itch reduction with SeS₂ at D3 than with 2% ketoconazole shampoo (onset at D7). Moreover, the subjects’ quality of life significantly improved after 28 days in both groups, with a faster improvement starting at D7 for subjects who received SeS₂ shampoo, compared to subjects who received ketoconazole shampoo (improvement at Day 14 only). Subjects highly appreciated the cosmeticity and efficacy of SeS₂ shampoo.

The present results obtained in this study are certainly due to the combination of 1% SeS₂ that acts on the Malassezia overgrowth and 0.9% salicylic acid, a keratolytic agent that reduces the number of scales. In a previous randomized study, SeS₂ shampoo served as a maintenance regimen for 2 months after an initial 4-week treatment with 2% ketoconazole formulation [21]. Results from this study showed that SeS₂ shampoo maintained the treatment outcome with ketoconazole, and maintained the improved scalp microbiota in subjects with SSD.

Even if no microbiota testing was performed in the present study, SeS₂ shampoo has proven a similar beneficial effect on the microbiota, especially on Malassezia spp., a key factor in SSD, showing reduced levels of scales, erythema, itching, and greasiness, which are all associated with SSD [1, 21, 23, 24]. In conclusion, SeS₂ shampoo is a cosmetic reliable and well-tolerated alternative care to 2% ketoconazole shampoo in the management of patients with moderate to severe scalp seborrheic dermatitis.

The authors acknowledge the study management support Anna Veriato, employee of Laboratoires Vichy International the time the study was conducted and the writing support of Karl Patrick Göritz, SMWS, France.

The study received local ethics committee approval (Phoenix, Mauritius (Independent Ethics Committee, August 4, 2022 and Rio de Janeiro, Brazil, Hospital Pró-Cardíaco-Esho Empresa De Serviços Hospitalares; 5.569.138, August 8, 2022) and all subjects provided written informed consent prior to inclusion.

Beatriz Sant’Anna and Stéphanie Leclerc-Mercier are employees of Vichy Laboratoires. The other authors have no conflict of interest to disclose.

This study was funded by Vichy Laboratoires, France.

Vimi Lutchmanen-Kolanthan and Anna Veriato conducted the study. Beatriz Sant’Anna and Stéphanie Leclerc-Mercier are sponsor representatives and contributed to the design of the study. Victoria Barbosa, Daniel Fernandes Melo, Sergio Vañó-Galván, and Pascal Reygagne served as consultants for this study. All authors read and approved the manuscript.

The corresponding author Stéphanie Leclerc-Mercier will, upon reasonable request, share the study protocol and all data collected and statistically analyzed and in relationship with this study, except de-identified participant data, for 1 year after publication of this manuscript. The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants.