Open‐label, single‐arm, single‐center clinical study on the effectiveness and safety of a moisturizer containing tocotrienol‐rich composition in children with mild to moderate atopic dermatitis

Abstract

Background

Little is known about antioxidant efficacy of topical vitamin E on atopic dermatitis (AD) due to lack of controlled clinical studies.

Aim

The study evaluates the effectiveness and safety of a topical moisturizer containing tocotrienol‐rich composition over 12 weeks on patients aged between 1 month and 12 years with mild to moderate AD.

Methods

We conducted a 12 weeks, prospective, open‐label clinical study on the effect of tocotrienol as an adjunct to conventional treatment. This study was approved by the Ethics Committee for Research Involving Human Subject. JKEUPM‐2019‐274 (NMMR‐19‐1588‐49234).

Results

Thirty AD patients with a mean age of 2.77 ± 3.05 were enrolled in the study. At week‐12, significant reduction of investigator global assessment (63.4%), Patient‐Oriented Scoring Atopic Dermatitis Index (PO‐SCORAD) (65%), and SCORAD (52.3%) was noted (p < 0.05). There was also a significant decreased in pruritus intensity (46%, p < 0.05). Similarly at week‐12, Infant's Dermatitis Quality of Life Index and Children's Dermatology Life Quality Index were found to improve significantly compared to baseline (p < 0.05). Instrumental assessment revealed improvement in TEWL and erythema index, 49.7% and 17.4%, respectively. No adverse reaction was observed. 95% of patients were satisfied with the moisturizer and 90% perceived it to be better than the one in the market. There was a 55.07% reduction in the use of hydrocortisone 1% cream toward the end of the study (p < 0.05).

Conclusions

The results suggested that tocotrienol‐rich moisturizer is safe and effective in the management of AD in young children.

INTRODUCTION

Atopic dermatitis (AD) is the most common form of eczema characterized with chronic pruritic, relapsing form of skin inflammation, which is primarily localized to the flexural surfaces of body, face, eyelids, neck, external auditory meatus, and limb flexures. Globally, AD affects up to 3% adults and 20% of children, and it is associated with an increment of 2- to 3-folds in developing nations. Despite the broad range of drugs (corticosteroids) available, patients are often dissatisfied with the treatments due to the risk associated with long-term usage. Topicals such as moisturizers are the first-line therapy in AD due to lower risk of adverse effects than the systemic medications used.

Natural phenolic antioxidants such as vitamin E is an added lipophilic compound of skin care products due to its dermatological benefits. It was suggested that vitamin E plays a vital role in inhibiting lipid peroxidation and stabilizing lipid bilayers of stratum corneum. Tocotrienols and tocopherols are the biologically active form of vitamin E, which are different in their aliphatic tails. The latter exhibited a superior antioxidant activity as it contains an isoprenoid instead of a phytyl side chain. The hydroxyl group on the chromanol ring acts to quench chain-carrying lipid peroxyl radicals on skin during oxidative stress. In fact, skin is a multi-layered tissue composed of continuously renewing keratinocytes at epidermis while underlying dermis is mainly made up of fibroblasts. In relation to this, vitamin E performs upregulation of gene expression of keratinocyte differentiation, indicating its therapeutic effect against AD. On the other hand, the topical use of vitamin E has also raised concerns about allergic contact dermatitis (ACD) in AD patients. Contact allergy due to vitamin E and its derivatives, mainly the synthetic form, has been described in a few individual case reports. Although vitamin E has been described as the cause of the ACD in some sporadic cases, the incident rate is fairly low despite its widespread use.

Despite its emerging use in skincare formulations, little is known of its antioxidant efficacy on AD due to lack of controlled clinical studies. Thus, the aim of the present study is to access the effectiveness and safety of a topical moisturizer containing tocotrienol-rich composition (REMDI® Sensitive Intensive Moisturising Cream; RS) on 1 month–12 year children with mild to moderate AD in a period of 12 weeks.

METHODS

Study participants

Children (1 month–12 years old) were recruited through three routes. First, patients who saw the trial advertisements on bulletins made available in UPM (specifically Pusat Kesihatan Universiti, Hospital Pengajar UPM's Family Medicine Clinic, Medical Specialist Clinic, or Pediatric Clinic) that contacted the sponsor voluntarily. Patients who saw the trial advertisements in social media, specifically Malaysia Eczema Support Community on Facebook, that contacted the sponsor voluntarily and patients who obtained words of mouth of the trial that contacted the sponsor voluntarily during the period of July 1, 2019–August 30, 2019.

Recruitment process were done from September 2019 to October 2019, followed by the study from November 2019 to February 2020 (4 weeks follow-up). The participants that completed the interventions were 30 patients due to three lost to follow-up and four participants withdrawn prematurely due to non-compliance. The sample size calculations were performed according to Cheon et al. where the mean difference and standard deviation of the SCORAD index will be 10 and 13.576, respectively. Using 80% power and a 5% significance level, the required sample size will be corrected to at least 29 participants for this trial.

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All informed consent was signed and obtained from the parent or guardian before starting the study. Eligible participants included those who are diagnosed with mild (IGA score = 2) to moderate (IGA score = 3) AD; at least 5% of body surface areas affected during the inclusion time; with a carer-reported pruritus score based on VAS of at least 4 and above; without other chronic health conditions such as asthma or allergic rhinitis; were free of dermatological disorders other than AD that would interfere with the assessment of treatments such as psoriasis, rosacea, or erythroderma. Exclusion criteria included those who are diagnosed with severe AD (IGA score = 4); secondary infection of AD; any physical attributes or skin conditions that might interfere with the clear visual or instrumental assessment (e.g., cuts or sunburn); with diabetes, severe liver disability (2.5-fold the normal high range value for ALT, AST), or severe renal disability (eGFR < 30 mL/min/1.73 m²); with immunodeficiency disorder or infectious disease (e.g., hepatitis, tuberculosis, HIV or AIDS, lupus, and rheumatoid arthritis); who are not keen to start on corticosteroid on screening; use of steroids, oral antibiotics, or immunosuppressants or physical therapy that could affect AD within 30 days or five half-lives; history of drug abuse, hypersensitivity to vitamin A, vitamin C, vitamin E, or oil palm-derived products; taking medication which could interfere with test results; poorly controlled bronchial asthma as mentioned according to GINA guideline.

Study sample

The study sample used (REMDI® Sensitive Intensive Moisturising Cream; RS) is a nonsteroidal topical cream containing natural vitamin E which comes in mixed isoforms of α-, β-, γ-, and δ- tocopherols and tocotrienols, as well as 3-O-ethyl ascorbic acid as the main ingredient. The remaining ingredients includes mineral oil, glycerin, hydroxyethyl urea, cetearyl alcohol, cera alba (beeswax), hydroxylethyl acrylate/sodium acryloyldimethyl taurate copolymer, ceteareth-25, butylene glycol, Olea europaea (olive) fruit oil, petrolatum, sodium levulinate, sodium anisate, polysorbate-80, beta-carotene, betaine, sodium hyaluronate, Aloe barbadensis leaf juice, caprylyl glycol, and carbomer. The vitamin E nanoemulsions used in the REMDII® formulation exhibited an average droplet sizes <150 nm based on the preliminary study. The nanoemulsified tocopherol and tocotrienol achieved a narrower size distribution and reduced dispersed phase density which can penetrate skin better and has greater skin therapeutic retention. Besides, the product is formulated at a slightly acidic range; pH 5–5.5, which is the natural skin pH.

Clinical protocol

This is a 12 weeks, prospective, open-label clinical study conducted in the Clinical Research Ward of Universiti Putra Malaysia Teaching Hospital. The study was conducted from November 2019 to February 2020. Permission for the human subject study was granted by the Ethics Committee For Research Involving Human Subject, JKEUPM-2019-274 (NMMR-19-1588-49234). In order to keep topical treatments consistent, participants were instructed to exclusively use the moisturizer (REMDII® Sensitive Intensive Moisturising Cream, RS) and body wash (REMDII® Sensitive Calming Body Wash) given and were abstained from using other soap-based products and commercial moisturizer during the whole study period. In accordance with this, participants were advised to apply the study product (RS) thrice daily on the affected AD lesion sites for 12 consecutive weeks. To ensure their compliance, each participant was requested to return the bottles at every visit to assess the amount of applied moisturizer. Mild potency corticosteroids such as hydrocortisone 1% cream was used for the first 2 weeks concurrently with the study product. Thereafter, the use is only limited to flare up. The utilization of corticosteroids were recorded in the provided diary.

Outcome measure

Physician based severity measurement, namely investigator global assessment (IGA), and Scoring Atopic Dermatitis Score (SCORAD) were used. Patient's directed severity measurement was assessed using Patient-Oriented Scoring Atopic Dermatitis Score (PO-SCORAD). Patients' quality of life improvement were measured using Children Dermatology Life Quality Index (CDLQI) or Infant Dermatitis Quality of Life (IDQOL). We objectively assessed the skin color and trans-epidermal water loss (TEWL) using a skin analyzer (Dermalab Series SkinLab Combo). These outcome measures were assessed at five different time points, namely baseline (week-0, week-2, week-4, week-8 and week-12). Toward the end of the study, subjects were asked to assess the satisfaction and opinion of the efficacy of the cream in comparison to other cream used in the past.

SCORAD

Severity Scoring of Atopic Dermatitis Index (SCORAD) is a composite severity index combining objective criteria and subjective symptoms (sleep loss and pruritus). Based on the SCORAD index, AD is classified into mild eczema score (<25), moderate eczema score (25–50), and severe eczema score (>50).

PO-SCORAD

Patient-oriented SCORAD (PO-SCORAD) is a self-assessment scale for atopic patients for evaluating severity of AD lesions, intensity of itch, and sleep disturbance. It involves the patient/parents directly in the monitoring of chronic AD, allowing them to evaluate the AD based on subjective and objective criteria derived mainly from the SCORAD.

IDQOL and CDLQI

Infants' Dermatitis Quality of Life Index (IDQOL) and Children's Dermatology Life Quality Index (CDLQI) were used to assess the quality of life (QOL) of patients. IDQOL questionnaire is designed for use in infants with AD below the age of 4 years while CDLQI questionnaire is designed to measure the impact of AD on the lives of children above 4 years.

Measurement of trans-epidermal water loss

TEWL of the test sites using TEWL probe in duplicates, expressed as grams of water per square meter per hour (g/m² h). It is based on the diffusion of water through the skin due to the water vapor pressure gradient between the skin surface and the ambient air. Prior to measurement, all patients were allowed to equilibrate in a closed environment with a constant temperature (20°C ± 2°C) and humidity (45%–55% RH). The same skin areas were recorded and assessed each time.

Measurement of skin color and erythema

Skin analyzer (Dermalab Series SkinLab Combo) is used to measure the skin color and erythema intensity of the test sites using color probe in duplicate, indicating L*, a*, b* result where L* refers to color luminosity, a* refers the color range from green (−) to red (+), and b* refers the color range from blue (−) to yellow (+). Erythema is expressed in arbitrary units. The same areas were recorded and assessed each time. Erythema is one of the skin parameters evaluated using non-invasive procedure. Red color of the skin indicated the sign of inflammation and acute stage of AD. Hence, changes in a* value from green (−) to red (+) was correlated to erythema intensity. The higher the a* value, the intense the erythema intensity.

Pruritus

Pruritus intensity is determined by the 10-point visual analogue scales (VAS), where 0 indicates none itching and 10 indicates the worst itching. This was found in SCORAD.

Statistical analysis

All experiments were conducted in triplicates and the experimental data were analyzed based on one-way analysis of variance (ANOVA) using Minitab Statistical Software Release 16 (Minitab Inc.). The differences between the means were considered significantly different at p < 0.05, as determined by Tukey's test.

RESULTS

Demographic

A total of 37 subjects were screened between September 2019 and October 2019 (Figure ). Seven subjects were withdrawn prematurely due to non-compliance (N = 3) and lost to follow-up (N = 4). As shown in Table , the subjects were mainly females (M:F 4:6), with a mean age of 2.77 ± 3.05 years. They had a mean IGA of 2.37 ± 0.49 and a SCORAD of 35.43 ± 14.19. The PO-SCORAD was 48.88 ± 17.81, and the CDLQI/ IDQOL was 12.90 ± 5.35. They have a mean pruritus score of 6.77 ± 2.01.

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TABLE 1 Demographics of the study population.

Parameters	N	%
Number of participants	30	100.0
Age (years)	2.77 ± 3.05	-
Gender
Male	12	40.0
Female	18	60.0
Week-0 (Baseline)
IGA	2.37 ± 0.49
SCORAD	35.43 ± 14.19
PO-SCORAD	48.88 ± 17.81
CDLQI/IDQOL	12.90 ± 5.35
Pruritus	6.77 ± 2.01

IGA

IGA showed a significant reduction at week-12 compared to the baseline (p < 0.05) with an overall improvement rate of 63.4% at the end of the treatment period as indicated in Figure . At week-2, the average values of IGA (1.67 ± 0.66) showed a statistically significant reduction (p < 0.05), compared to baseline (2.37 ± 0.49).

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SCORAD and PO-SCORAD

As shown in Figure , AD improved over the study period, with a decrease of SCORAD and PO-SCORAD scores from week-0 to week-12. The resulting mean SCORAD score decreased from 35.43 ± 14.19 (week-0) to 12.39 ± 9.35 (week-12) significantly (p < 0.05), with a relative reduction of 65%. Similarly, PO-SCORAD score decreased pronouncedly by 52.3% from 48.88 ± 17.81 to 23.31 ± 15.52 across the treatment period, with a significant difference (p < 0.05).

IDQOL/CDLQI

As shown in Figure , both IDQOL/CDLQI demonstrated a decreasing trend across the study period suggesting an improvement in quality of life of the enrolled AD patients. The mean baseline of IDQOL/CDLQI was 12.90 ± 5.34. After 2 weeks, IDQOL/CDLQI was significantly (p < 0.05) reduced by 45% compared to the baseline (7.07 ± 3.77). At week-12, IDQOL/CDLQI score was 5.33 ± 3.98 which was significantly reduced by 58% compared to the baseline (p < 0.05).

Pruritus

A significant improvement of pruritus intensity was noted (p < 0.05), decreased from 6.77 ± 2.01 at week-0 to 3.63 ± 2.39 at week-12, with a relative reduction of 46.3% in 12 weeks' time as shown in Figure .

Skin color and erythema

As shown in Table , a* value of the patients decreased across the treatment periods significantly (p < 0.05), which indicated that the redness of the patients improved. Treatment with RS resulted in a progressive improvement of skin inflammation, as demonstrated by the change in the cumulative severity of erythema index. The erythema index of the AD patients showed a decreasing trend across the study period. As depicted in Figure , the mean value of erythema index exhibited was 12.53 ± 2.24 at week-12 compared to baseline (15.17 ± 2.49) with a significant reduction of 17.4% (p < 0.05).

TABLE 2 Mean values of skin color (L*a*b*) of the patients across the study period.

Week	Color
L*	a*	b*
Week-0	28.26 ± 5.05a	15.89 ± 1.90a	12.25 ± 2.50a
Week-2	26.55 ± 4.79ab	15.42 ± 1.35ab	12.43 ± 2.3 ab
Week-4	28.75 ± 5.50ab	14.78 ± 1.33bc	13.54 ± 1.98bc
Week-8	29.53 ± 4.77ab	14.06 ± 1.44cd	14.20 ± 1.92c
Week-12	30.55 ± 5.09b	13.31 ± 1.54d	15.21 ± 1.7c

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Trans-epidermal water loss

The trans-epidermal water loss (TEWL) of the AD patients across the study week is depicted in Figure . At week-0, the mean TEWL exhibited was 24.26 ± 11.33 g/m² h which further reduced to 12.21 ± 6.01 g/m² h at week-12 significantly (p < 0.05), with relative reduction of 49.7%.

Questionnaire

The assessment of the overall satisfaction of RS was determined using a study-specific questionnaire administered to patients at week-12 (Table ). The cream was found to be well tolerated after application. There was no adverse reaction observed in the form of redness, swelling, dryness, itching and burning sensation. The results showed that approximately 95% of patients perceived the study treatment (RS) as good or excellent in terms of overall satisfaction, and approximately 90% of patients regarded RS as better than commercial moisturizers used in the past.

TABLE 3 Patient-reported satisfaction score of REMDII Sensitive Intensive Moisturising Cream.

Overall satisfaction of RS	Number of participants	%
Excellent	18	60.0
Good	11	36.7
Fair	1	33.3
Poor	-	0.0
Opinion about efficacy of RS in comparison to commercial moisturizers used in the past
Better	28	93.3
Similar	2	6.7
Worst	-	0.0
Not applicable	-	0.0

Steroid usage

As shown in Figure , there was a significant reduction in the frequency of hydrocortisone application from baseline (9.46 ± 4.70) to study end (4.25 ± 4.86) with a significant reduction of 55.07% (p < 0.05).

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DISCUSSION

AD is strongly associated with keratinocyte damage and impaired skin barrier. It is widely accepted that reactive oxidants caused cellular damage to the epidermal keratinocytes via lipid peroxidation and further trigger tissue inflammation through genes upregulation accounted for pro-inflammatory cytokines via the nuclear factor-κB pathway. Treatment with topical antioxidants provides a non-invasive alternative to repair the underlying mechanisms of cellular and molecular damage from oxidative-free radicals in AD patients. Inflamed skin requires both hydrophilic and lipophilic antioxidants like vitamin C and E.

The lipophilic properties of vitamin E allows them to travel down to the deeper stratum corneum layer within the cell membranes through sebaceous gland secretions and protect them from oxidative damage. Vitamin E is delivered to the skin surface via sebum to protect the stratum corneum from the oxidative damage. 3-O-ethyl ascorbic acid which was used in this study is a potent chain-breaking agents with markedly affinity for biomembranes. It is absorbed easily through the skin than other ascorbic acid attributed to its lipophilic and hydrophilic properties. Thus, direct topical application of these antioxidants is expected to facilitate this protection.

Vitamin C (3-O-ethyl ascorbic acid) was shown to protect cells against UV-induced oxidative insult by scavenging free radicals and reactive oxygen species in vitro. Besides, vitamin E (α-tocopherol) at 20 and 40 μM was shown to improve barrier function by means of reduced TEWL compared to controls in vivo. 3-O-ethyl ascorbic acid is a stable l-ascorbic acid derivative with an ethyl group at third carbon position (C3). This biologically active form of vitamin C is a potent antioxidant and can protect the cells from oxidative damage by scavenging free radicals and reactive oxygen species. Besides, it helps in skin renewal by stimulating collagen biosynthesis, being co-factor for the formation of hydroxyproline and hydroxylysine.

Results showed that the erythema index of the AD patients reduced across the treatment period which could be explained by the deactivation of free radicals by both vitamin E and vitamin C where they interact synergistically to provide antioxidant protection. Vitamin E quenches lipid peroxyl radicals by donating hydrogen from their phenolic group and becomes oxidized. The resulting tocopheroxyl and tocotrienoxyl radicals will be reduced by the redox cyclers (vitamin C) with lower redox potential to rejuvenate its activity. The synergistic relationship provided 4-fold protection against erythema induced by solar-simulated irradiation after topical application. This helps to alleviate the oxidative stress on the inflamed skin. Similarly, previous study revealed a significant improvement of melasma and pigmented contact dermatitis lesions using a combination of topical vitamins E and C, which prove to be superior to the single-treatment groups.

Topical applications of vitamin E permeate the dermis and epidermis. Despite the fact that topically applied dose vitamin E is unstable and will be destroyed on the skin after exposure to UV light, nanotechnology could be used as an alternative to overcome to bioavailability problem of vitamin E. The incorporation of vitamin E nanoemulsion prepared using high pressure homogenizer was incorporated into the RS formulation; exhibited a mean droplet size of 150 nm was believed to improve the drug release profile and skin penetration attributed to the high interfacial area related to their nano-sized droplets. This is similar to the research by Akhtar et al. in which β-cycloethosomes developed based on β-cycloamylose and carbomer 934P gel with nano-size of 228.33 ± 1.23 nm is able to reach the deeper skin layers.

All enrolled AD patients experienced skin dryness with higher TEWL at week-0. Across the treatment period, topical application of the treatment moisturizer containing the vitamin E increased the stratum corneum hydration and improved the water binding capacity. Generally, an average TEWL of a healthy skin lies between 0 and 15 g/m² h. Hence, it was evidenced that the enrolled AD patients exhibited higher TEWL associated with an impaired skin barrier function with more water lost to the ambient air. In average, the TEWL of all AD patients fell between the ranges of healthy skin TEWL at week-12. Hence, it is postulated that topical vitamin E could improve skin water-binding capacity. This is in line with the previous study by Gönüllü and co-workers, which indicated that tocopherols containing emulsion exhibited higher skin conductance than calcium ascorbate and ascorbic acid containing emulsion, suggesting that vitamin E exhibited better skin hydration compared to vitamin C. Another study suggested that topical vitamin E enhanced the hygroscopicity and water holding capacity of the stratum corneum by enhancing the ceramide synthesis. It induced the differentiation of epidermal keratinocytes by increasing Ca²⁺ uptake and stimulating gene expression of ceramide synthetase (serine palmitoyltransferase) and led to increment of ceramide content in stratum corneum. This results in improved skin barrier moisture-retention.

Surface skin pH lies in the range of 4–6, inherently acidic in nature. It is a major factor in maintaining skin barrier integrity. Elevated surface skin pH is a hallmark of AD, rendering the skin more susceptible to irritation. It was evidenced that lesional skin on AD patients often exhibit 0.1–0.9 pH units higher indicating a shallower pH gradient. Harsh alkaline detergents over the skin will alter the skin's acidic pH and dysregulates downstream enzyme activity and triggers AD. Both RS and BW (REMDII® Sensitive Calming Body Wash) are formulated with mild acidic pH range (5.0–5.5) and this could help to normalize the skin pH to its usual acidic range. Same result has been reported that low pH cleanser (pH 3.5) enhanced AD severity clinically in terms of Eczema Area and Severity Index, CDLQI, and pruritus index.

Topical corticosteroids such as hydrocortisone (1%) was allowed in this study for patients based on prescription of doctor. It is a mild topical corticosteroid used to treat swelling, redness and itchiness for skin inflammatory. However, the clinical usefulness of topical hydrocortisone is restricted with minimum usage in this study due to their propensity to induce dermal thinning. As shown in Figure , there was a significant reduction in the frequency of hydrocortisone application from baseline (9.46 ± 4.70) to study end (4.25 ± 4.86) with a significant reduction of 55.07% (p < 0.05). Similar result has been highlighted whereby medium-potency topical corticosteroids when used in combination with emollients were found to minimize the relapsing risk for children with moderate to severe AD. The limitations of the study includes of the lifestyle factors of the patients; which may lead to imprecise results and the small sample size (N = 30). Besides, it is a non-randomized, single arm and open labeled study which may reduce the reality of the data.

CONCLUSION

Most of the AD patients in this study observed an improvement in clinical symptoms, with reduction of pruritus intensity measured through SCORAD index; PO-SCORAD; IDQOL/CDLQI. IGA scores indicated no adverse events. The overall improvement in terms of TEWL and erythema index also makes the tocotrienol enriched moisturizer used within the study a safe and effective moisturizer for management of AD in young children.

AUTHOR CONTRIBUTION

All authors contributed equally to this work.

ACKNOWLEDGMENTS

The study design, data collection, analysis, interpretation of results, study-approved treatment moisturizer, and non-soap wash used by the subjects were funded by Lipidware Sdn. Bhd. All authors had full access to all the data in this study. The authors would like to thank Teaching Hospital Universiti Putra Malaysia for the use of the Clinical Research Ward and staff and facilities throughout the clinical trial.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ETHICS STATEMENT

This study was approved by the Ethics Committee for Research Involving Human Subject. JKEUPM-2019-274 (NMMR-19-1588-49234).

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