Essential

Oil and Benzoin Cream an Effective Treatment of Mild to Moderate Eczema and Atopic Dermatitis: Results From a Randomized, Double Blind, Placebo Controlled Study
Belinda Pilmore, BNat.Ther, Dip Cos Sci; Mariza Ovalle, BSc. Study conducted by third party: Institute of Personal Care Science __________________________________________________________________________________ ABSTRACT Objective. This study was designed to evaluate the effectiveness of a cream containing benzoin and essential oils of Lavender and Citrus Sinensis Peel for the treatment of mild to moderate eczema/atopic dermatitis (AD). Methods. A total of 54 participants (4 months 84 years old) with mild to moderate eczema/AD were randomized to receive Natzema or placebo 3 times daily in a 28 day double-blind study. Efficacy was evaluated using the Eczema Area and Severity Index (EASI score) at baseline, day 7 and day 28. Results. At the end of the study, the participants using the active substance showed an average improvement of 63.6% (71.4% (20 of 28) of the participants on active completed the trial) using the EASI score system. This was extremely statistically significant compared to the placebo group, which showed an average worsening of symptoms of 10.54% (73.1% (19 of 26) of the participants on placebo completed the trial) using the EASI score system. The eczema of 30% of participants in the active group cleared up completely within the 28 day test with a further 65% of participants in the active group showing a 30% or greater improvement in the symptoms and area affected by their eczema. Only 1 participant (5%) from the active group who completed the trial did not show any improvement. There were no adverse events reported by those in the active group to the product. Conclusion. Natzema containing benzoin and essential oils of Lavender and Citrus Sinensis Peel is a safe and effective treatment for mild to moderate atopic eczema and AD. __________________________________________________________________________________ Eczema, also known as atopic dermatitis (AD)1, is an inflammatory condition affecting the epidermis. Eczema tends to be more prevalent in children2, 3. It is estimated that in Australia, eczema currently affects 1 in 6 children aged up to 6-7 (17%), 1 in 10 children up to ages 13-14 (10%), and 1 in 14 (7%) adults. The prevalence in other Western countries is similar: 7 17% of school aged children are affected by AD4; while in the UK, as many as 1 in 5 (20%) school aged children are affected by the condition5. Symptoms of mild to moderate eczema/AD include dryness of the skin with rashes, persistent itching, flaking and cracking; and in more severe cases, the skin may also blister, swell and ooze3. The skin commonly appears red with complete coverage or spotted in areas, and may appear thicker than usual (lichenification or epidermal thickening). June 29th, 2012 Version 1.0 Page 1

The itching associated with eczema/AD leads to other issues affecting the sufferers: sleep disturbances and deprivation; irritability resulting from the itching and/or poor sleep; absences at school or work; medical expenses associated with treatments and self-consciousness due to appearance of the skin and/or itching4-9 Treatment includes the use of topically applied corticosteroid creams and ointments aimed at reducing the symptoms10-12. It has been found, however that the prolonged use of corticosteroid products can lead to systemic absorption and side effects, including atrophy (thinning and fragility of the skin) and immunosuppression of the local area which can lead to skin infections, particularly where the skin is broken when scratched. Using moisturisers to keep the skin moist to reduce the severity of itching and dryness is another method commonly used although may not provide significant relief in many users. Avoiding soaps and detergents that dry the skin can also help lessen the symptoms in some suffers. Due to the exceedingly high prevalence of eczema/AD and undesirable adverse events of long term use of corticosteroids, a cream using natural ingredients for the base and empirically known traditional ingredients as actives was developed to help relieve the symptoms of mild to moderate medically diagnosed eczema/AD. Natzema was developed and formulated using traditional remedies of Citrus Sinensis Peel and Lavender essential oils combined with benzoin tincture to provide a natural alternative to medicinal eczema treatments. This study was designed to investigate the efficacy of the Natzema to treat participants with mild to moderate atopic eczema. METHODS Study Design and Conduct This was a randomized, double-blinded, placebo controlled study conducted between April and June, 2012. Eligible participants were randomized using a computer generated random numbers list to receive either Natzema or placebo. Investigators were blinded to treatment. The active product contained essential oils which gave it a distinct aroma, however only participants using the active product were aware of any aroma. They were not aware that the placebo carried no aroma. The placebo product was identical in colour and consistency to the base of the active product, however there was no smell associated with the placebo product. Investigators were blinded to any aroma during the trial period and participants using product were blinded to the presence or absence of aroma in product they were not assigned to. All participants or their legal guardians gave written informed consent before enrolment in the trial. Participant Selection Participants that were selected had been medically diagnosed mild to moderate eczema. The degree of severity was rated using the EASI score system. Participants were excluded from the study if they had a skin disorder other than atopic eczema in the area to be treated, if their eczema/AD was currently under control or if they were pregnant or nursing. June 29th, 2012 Version 1.0

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Treatment Plan Participants were required to apply (or in the case of babies and young children, have applied) a thin coating of product to the affected area, 3 times daily, for 28 days. They were not permitted to use any other medications, oral or topical, or other treatments, during the trial. The application of non- medicated moisturisers was permitted on areas not being treated. Primary Outcome Measures The EASI score is a tool used to measure the severity and extent of atopic eczema. It divides the body into four regions: 1. Head and neck; 2. Upper limbs; 3. Trunk; and 4. Lower limbs. The intensity of a representative area of eczema and the approximate percentage affected by eczema are calculated for each region.

Figure 1: Pictorial representation of EASI Score System; reproduced from http://dermnetnz.org/dermatitis/easi.html All outcome measures were assessed at baseline/day 1, day 7 and day 28. Safety Outcome Measures Although not an official outcome of this study, interviews with participants were conducted to evaluate the nature and extent of any adverse events with the use of either the active substance or placebo. No adverse events were reported by any participants for either product. Statistical Analysis The Primary Outcome Measure was analysed by comparing the day 28 results of both groups using an unpaired t-test with a significance level of = .05. June 29th, 2012 Version 1.0 Page 3

RESULTS Participant Accounting 54 participants were enrolled in the study; 28 in the active group and 26 in the placebo group. Only those who completed the study were included in the efficacy analyses. A total of 71.4% (20 of 28) of the participants on active completed the trial while 73.1% (19 of 26) of the participants on placebo completed the trial. The reasons for withdrawal from the study are shown in Figure 2. Withdrawal resulting from self-proclaimed total recovery occurred in 75% of participants in the active group compared with 0% of participants in the placebo group. Withdrawal resulting from lack of efficacy occurred in 100% of participants in the placebo group. Because these were self-proclaimed results by participants and not that of the investigators, these outcomes were not used in the statistical analysis. Participant Code PE005-F PE005-H PE005-X PE005-AD PE005-AE PE005-AF PE005-AJ PE005-AQ PE005-G PE005-L PE005-T PE005-Z PE005-AA PE005-AI PE005-AX Treatment Group Active Active Active Active Active Active Active Active Placebo Placebo Placebo Placebo Placebo Placebo Placebo Reason for leaving study Cessation of symptoms saw no reason to return Cessation of symptoms too difficult to return (family reasons) Would not allow caregiver to apply cream Cessation of symptoms too difficult to return (work commitments) Cessation of symptoms saw no reason to return Unable to contact Cessation of symptoms saw no reason to return Cessation of symptoms saw no reason to return Not happy with results; discontinued trial Not happy with results; reverted to previous steroid treatment Not happy with results; discontinued trial Not happy with results; discontinued trial Not happy with results; discontinued trial Not happy with results; reverted to previous steroid treatment Not happy with results; reverted to previous steroid treatment Figure 2: Reasons from withdrawing from study

Participant Demographics and Baseline Characteristics Participant demographics and baseline characteristics were compared between the two groups. The average age for the active group was 27.1 years and for the placebo group was 32.6 years. This difference was not considered to be statistically different (P=0.2793) The EASI score of participants in the active group started significantly higher than in the placebo group (average EASI score was 6.86 and 1.9 respectively; P=0.0036). All participants were Caucasian. Active Placebo Male % 57.1 61.5 Female % 42.3 38.5 Age, mean 27.1 32.6 Age range 4 months 84 years 2.5 years 65 years EASI score, mean 6.86 1.9 EASI score range 0.6 36.4 0.4 4.2 Figure 3: Participant Demographics and Baseline Characteristics June 29th, 2012 Version 1.0 Page 4

Efficacy After 7 days, the average improvement in EASI score amongst participants in the active group was 21.68%. This compared to an average worsening of EASI score in the placebo group of 11.78%.
25.00% 20.00% 15.00% 10.00% 5.00% 0.00% Day 7 -5.00% -10.00% -15.00% -11.78% Natzema Placebo 21.68%

Figure 4: % improvement in EASI score after 7 days After 28 days, the average improvement in EASI score amongst participants in the active group was 63.6%. This compared to an average worsening of EASI score in the placebo group of 10.54%.
70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% 7 Days -10.00% -20.00% -11.78% -10.54% 28 Days 21.68% Natzema Placebo 63.60%

Figure 5: % improvement in EASI score after 7 and 28 days

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The overall success rate, defined as the percentage of participants who completed the trial achieving a greater than 30% EASI score improvement in their eczema/AD within 28 days, was extremely statistically significant in participants treated with the active product (n = 19 out of 20; 95%) compared with those on the placebo product (n = 1 out of 19; 5%). A total of 71.4% (20 of 28) of the participants on active completed the trial while 73.1% (19 of 26) of the participants on placebo completed the trial. Withdrawal resulting from self-proclaimed total recovery occurred in 75% of participants in the active group compared with 0% of participants in the placebo group. Withdrawal resulting from lack of efficacy occurred in 100% of participants in the placebo group. DISCUSSION In this study, the majority of participants presented with mild to moderate eczema/AD. At day 7 and 28, the average improvement in EASI score and percentage of participants with treatment success was significantly greater in the active group than it was in the placebo group. There was a relatively high drop-out rate in both groups; but the reasons for drop-out varied significantly. Of the 8 participants (28.6%) in the active group who did not complete the study, most of these dropped at the 7-day point because of self-reported cessation of symptoms who did not see the need to continue the study. Only one participant could not be contacted for comment while one other did not submit to treatment. All of the 7 participants in the placebo group who did not complete the study dropped because they did not believe the product was working and/or reverted to steroid or other therapy to manage their symptoms. The placebo product was an emollient base without the actives contained in the active product but did not show improvement. This showed that no significant benefit to EASI score ratings resulted from the application of a moisturiser with emollient base, but that instead, results were obtained using the active ingredients. The extremely statistically significant results obtained from this trial and nil reports of adverse events showed that the active cream provided benefits without side effects from Natzema. CONCLUSIONS This study demonstrates that Natzema containing benzoin and essential oils of Lavender and Citrus Sinensis Peel essential oils is an effective treatment of mild to moderate eczema/AD. It provided effective relief to 95% of participants with an average improvement of 63.6% within 28 days. The results were extremely statistically significant and displayed no adverse events. It can be used for the effective treatment of medically diagnosed mild to moderate eczema/AD without the potential long-term consequences of topical corticosteroids, and provides a steroid-free alternative to medically prescribed eczema/AD treatments.

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REFERENCES 1 Bershad, SV (2011 Nov 1). In the clinic. Atopic dermatitis (eczema). Annals of internal medicine. 155 (9): ITC51-15; quiz ITC516. 2 Allergies in Australia. April, 2011. http://www.allergycapital.com.au/allergycapital/Allergies_in_Australia.html 3 Facts About Eczema. Eczema Association of Australasia. Accessed June 2012. http://www.eczema.org.au/info/facts.html 4 Schachner et al., (2005). Tacrolimus Ointment 0.05% Is Safe and Effective for the Treatment of Mild to Moderate Atopic Dermatitis in Pediatric Patients: Results From a Randomized, Double-Blind, Vehicle-Controlled Study. Pediatrics. 116 (3):334 - 342 5 Lawton S, van Onselen J. Atopic eczema in primary care, Prescriber Supplement,1999. 6 Paller AS, McAlister RO, Doyle JJ, Jackson A. Perceptions of physicians and pediatric patients about atopic dermatitis, its impact and its treatment. Clin Pediatr (Phila). 2002;41:323-332. 7 Bender BG, Leung SB, Leung DYM. Actigraphy assessment of sleep disturbance in patients with atopic dermatitis: an objective life quality measure. J Allergy Clin Imunol. 2003; 111:598-602 8 Drake L, Predergast M, Mather R, et al. The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol. 2001;44:S65-S72 9 Chamlin SL, Frieden IJ, Williams ML, Chren M. Effects of atopic dermatitis on young American Children and their families. Pediatrics. 2004;111:607-611. 10 Hoare C, Li Wan Po A, Williams H (2000). Systematic review of treatments for atopic eczema. Health Technology Assessment 4 (37): 1191. 11 Atherton DJ (October 2003). Topical corticosteroids in atopic dermatitis. BMJ 327 (7421): 9423. 12 Lee NP, Arriola ER (1999). Topical corticosteroids: back to basics. The Western Journal of Medicine 171 (5-6): 3513.

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