Tea tree oil gel for mild to moderate acne; a 12 week uncontrolled, open-label phase II pilot study

Australasian Journal of Dermatology (2017) 58, 205 210 doi: 10.1111/ajd.12465 ORIGINAL RESEARCH Tea tree oil gel for mild to moderate acne; a 12 week uncontrolled, open-label phase II pilot study Harsimran Kaur Malhi, 1 Jenny Tu, 2 Thomas V Riley, 3,4 Sujith Prasad Kumarasinghe 2,5 and Katherine A Hammer 4 1 Department of General Medicine, St John of God Hospital, Perth, Western Australia, 2 Department of Dermatology, Royal Perth Hospital, Perth, Western Australia, 3 PathWest Laboratory Medicine WA, Queen Elizabeth II Medical Centre, Perth, Western Australia, 4 School of Pathology and Laboratory Medicine (M504), University of Western Australia, Perth, Western Australia, and 5 Hollywood Medical Centre, Perth, Western Australia, Australia ABSTRACT Background: The efficacy, tolerability and acceptability of a tea tree oil gel (200 mg/g) and face wash (7 mg/g) were evaluated for the treatment of mild to moderate facial acne. Methods: In this open-label, uncontrolled phase II pilot study, participants applied tea tree oil products to the face twice daily for 12 weeks and were assessed after 4, 8 and 12 weeks. Efficacy was determined from total numbers of facial acne lesions and the investigator global assessment (IGA) score. Tolerability was evaluated by the frequency of adverse events and the mean tolerability score determined at each visit. Product acceptability was assessed via a questionnaire at the end of the study period. Results: Altogether 18 participants were enrolled, of whom 14 completed the study. Mean total lesion counts were 23.7 at baseline, 17.2 at 4, 15.1 at 8 and 10.7 at 12 weeks. Total lesion counts differed significantly over time by repeated measures ANOVA (P < 0.0001). The mean IGA score was 2.4 at baseline, 2.2 at 4, 2.0 at 8 and 1.9 at 12 weeks, which also differed significantly over time (P = 0.0094). No serious adverse events occurred and minor local tolerability events were limited to peeling, dryness and scaling, all of which resolved without intervention. Correspondence: Dr Katherine A. Hammer, School of Pathology and Laboratory Medicine (M504), University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia. Email: katherine.hammer@uwa.edu.au Harsimran Kaur Malhi, MBBS. Jenny Tu, FACD. Thomas V Riley, PhD. Sujith Prasad Kumarasinghe, FACD. Katherine A Hammer, PhD. Conflict of interest: none. Submitted 3 December 2015; accepted 25 January 2016. Conclusion: This study shows that the use of the tea tree oil products significantly improved mild to moderate acne and that the products were well tolerated. Key words: alternative treatment, essential oil, in vivo efficacy, terpenes, propionibacterium, topical therapy. INTRODUCTION Acne is a common skin disease caused by a combination of factors including inflammation, excessive sebum production, abnormal desquamation of the follicular epithelium and an immunological response to Propionibacterium acnes. 1 Acne occurs primarily in adolescents and young adults with up to 90% of adolescents affected at some stage. 2 In addition, persistent or late onset acne occurs in adults, with prevalence rates higher than 50% reported in some studies. 3 Aside from discomfort and potential scarring, acne may cause severe emotional and psychological distress to sufferers. 4 Acne can be treated with a range of agents, either applied topically or taken orally. Major modes of action for common acne treatment agents are antimicrobial activity, anti-inflammatory action, the normalisation of follicular hyperkeratinisation and the reduction of sebum production. 1 Those with mild acne commonly elect to self-treat with over-the-counter acne treatment products and a recent study shows that products containing tea tree oil are a popular choice. 5 Tea tree oil is an essential oil Abbreviations: IGA MIC investigator global assessment minimum inhibitory concentration

206 HK Malhi et al. derived by steam distillation from the Australian plant Melaleuca alternifolia (Myrtaceae). Tea tree oil has been used medicinally in Australia since the 1920s and is currently used primarily as a topical antimicrobial or anti-inflammatory agent. 6 Several previous studies have demonstrated that tea tree oil products are beneficial for treating acne, with fewer acne lesions present after therapy. 7 Most previous trials have investigated products containing up to 5% (v/v) tea tree oil but most of these products are not available commercially. The aim of this study was therefore to evaluate the efficacy, tolerability and acceptability of a commercially available tea tree oil gel (200 mg/g) for the treatment of mild to moderate acne. PARTICIPANTS AND METHODS In vitro product evaluation Clinical isolates of P. acnes (n = 10) were obtained from PathWest Laboratory Medicine WA (Perth, WA, Australia). Susceptibility to tea tree oil (non-formulated), Tea Tree Medicated Gel for Acne (200 mg/g; AUST L 55740) and Tea Tree Face Wash for Acne (7 mg/g), both supplied by Thursday Plantation (Integria Healthcare, Brisbane, Qld, Australia) was determined using a standard broth microdilution method, 8 with the exception that a brain-heart infusion broth was used as the test medium. Products contained Australian tea tree oil meeting the specifications of the British Pharmacopoeia monograph for tea tree oil 9 and both ISO 4730:2004 and Australian 2782 2009 standards for Oil of Melaleuca, terpinen-4-ol type (tea tree oil). 10,11 Minimum inhibitory concentrations (MIC) of each product were determined visually after 48 h of anaerobic incubation and the assay was repeated in entirety thrice. Pilot study design This was a dual-centre, open-label, phase II pilot study conducted at two sites in Perth, Western Australia and approved by the Human Research Ethics Committees of Royal Perth Hospital, Hollywood Private Hospital and the University of Western Australia. The study was registered with ClinicalTrials.gov (identifier NCT01657110) on 1 August 2012. Participants Participants were recruited from January to September 2014 by placing posters at both study sites, placing notices in site newsletters and distributing the study notices to staff and students at the university. Eligible participants were of either sex, aged 14 45 years old, with mild to moderate facial acne defined as 10 100 facial lesions, and an investigator global assessment (IGA) score 12 of at least two and no more than two nodules. IGA scores were defined as 0, clear skin with no lesions; 1, almost clear with rare lesions; 2, mild severity with some non-inflammatory and no more than a few inflammatory lesions; 3, moderate severity with many non-inflammatory and some inflammatory lesions and 4, severe with many noninflammatory and inflammatory lesions with no more than a few nodules. Additional inclusion criteria were using adequate contraception and the ability to provide informed, written consent and comply with the study protocol. Exclusion criteria were a known allergy to tea tree oil, another current skin disease, current use of steroids or antibiotics, severe underlying disease, pregnancy, breast feeding and having participated in another clinical trial within the previous 12 weeks. Eligible participants provided their informed, written consent prior to inclusion. For minors (under 18 years of age), informed written consent was also obtained from the parent or legal guardian. Intervention The participants were allocated one 25 g tube of Tea Tree Medicated Gel for Acne (200 mg/g; AUST L 55740) and one bottle of Tea Tree Face Wash for Acne (7 mg/g), both supplied by Thursday Plantation (Integria Healthcare). The participants were instructed to self-patch test to confirm the absence of a tea tree allergy by applying a pea-sized amount of gel to the inner arm and leaving it on overnight. If no reaction was seen, the participants continued with the study. For treating facial acne, the participants were instructed to use the products twice daily by firstly washing their face with one pump of the face wash, patting it dry and then applying a pea-sized amount of gel in a thin layer to acne-affected areas. They were instructed to leave the product on for at least 6 h and wash it off only at the next application time. Additional products were supplied if required. Study assessments and outcomes Efficacy and tolerability was clinically assessed by the investigators at 4, 8 and 12 weeks. The participants were also contacted at 2 weeks to check their progress and protocol compliance. The primary efficacy end-points of IGA score and total lesion count (including inflammatory lesions, non-inflammatory lesions and nodules) were recorded at each visit. The secondary efficacy end-point of skin oiliness was also recorded by the investigator at each visit using a five-point scale where 0 was none, 1 was minimal, 2 was mild, 3 was moderate and 4 was severe. Study compliance and medication adherence were assessed via a diary sheet on which the participants recorded the time of day that they applied the products and by the investigator weighing the products at each visit. Participants were also asked to record at the end of each week whether they thought their acne was significantly worse, slightly worse, about the same, slightly improved or significantly better. The primary tolerability end-point was the frequency of adverse events. The secondary tolerability end-point was the mean local tolerability score, calculated as the mean of scores assigned by the investigator to the five signs and symptoms of erythema, scaling, peeling, induration and dryness. These were scored on a five-point scale where 0 was none and 4 was severe. Any parameters graded as 4

Tea tree oil products for acne treatment 207 RESULTS In vitro product evaluation For tea tree oil, the MIC ranged from 0.25% to 1% (v/v); 90% of isolates having been inhibited by 1%. For the tea tree oil gel, the MIC ranged from 0.31% to 2.5% (w/v) of the product, corresponding to a tea tree oil concentration range of 0.062 0.5%. The tea tree oil face wash inhibited the growth of all isolates at <0.25% (v/v) of the product. Participants disposition and baseline characteristics A total of 18 participants received the treatment (Fig. 1), of whom 78% (n = 14) completed the study. Of these, five were male and nine were female, with an age range of 16 39 years, a mean of 26 years of age and a standard deviation of 7 years. The participants had experienced acne for an average of 11 years. Of the four (22%) participants who were discontinued, two did so for protocol violations (commencement of new medications) and two did so at the participants request. Figure 1 Enrolment flow chart. were classified as an adverse event. Product acceptability was evaluated via a questionnaire completed by participants at the final visit which had 10 questions covering product characteristics, usability and their overall impression. Statistical analyses Data from the per protocol population (n = 14) were analysed by a repeated measures ANOVA with a Bonferroni post-test. The last observation carried forward method was used to handle missing values. The level of significance for all tests was set at 0.05. Efficacy evaluation The mean total lesion count was 23.7 (range 12 72) at baseline, 17.2 at 4 (range 6 48), 15.1 at 8 (range 5 51) and 10.7 (range 1 23) at 12 weeks (Fig. 2a). The mean percentage decreases in total lesion count from baseline were 25% at 4, 37% at 8 and 54% at 12 weeks. Total lesion counts at each visit differed significantly by a repeated measures ANOVA (P < 0.0001). Post-hoc tests showed that the total lesion counts differed significantly from baseline at 4 (P < 0.05), 8 (P < 0.01) and 12 weeks (P < 0.001). The IGA score (Fig. 2b) decreased from a mean of 2.4 at baseline to 2.2 at 4, 2.0 at 8 and 1.9 at 12 weeks. The scores differed significantly from baseline at 8 (P < 0.05) and 12 weeks (P < 0.05). The mean score for facial oiliness Figure 2 Efficacy parameters of (a) mean numbers of lesions (standard error of the mean) and (b) investigator global assessment (IGA) scores shown in a box-whisker plot. The boxes indicate the 25th 75th percentile, and whiskers indicate the maximum and minimum values. The + symbol indicates the arithmetic mean and the heavy horizontal line indicates the median.

208 HK Malhi et al. was 2.0 (mild) at baseline, 2.2 at 4, 1.6 at 8 and 1.1 at 12 weeks, which differed significantly by ANOVA (P = 0.0004). Post-hoc tests showed that the change from baseline was statistically significant at 12 weeks only (P < 0.01). Clinical efficacy was defined in the protocol as a reduction in total lesion count of 40% or more at 12 weeks. According this criterion, the products were clinically effective in 11 (79%) participants. Medication adherence data from diary sheets was complete for all 12 weeks for 11 (79%) participants and partially complete for the remainder. Overall, adherence was high, with a mean application rate by participants of 96% (6.1%) and a range of 81 100%. The mean total weight of gel used per participant was 27.7 g (range 4.9 55.1 g). The total amount of gel used did not correlate with total number of gel applications or baseline numbers of acne lesions, suggesting that those who were 100% protocol compliant or those with the most severe acne were not necessarily those who used the most gel. The mean weight of the face wash used was 123.7 g (range 68.8 221.5 g). At the end of each week, participants indicated on their diary sheets their opinion on whether their acne severity had changed compared with the previous week. The maximum possible number of responses from the per-protocol population was 168 (14 participants multiplied by 12 weeks), and 132 responses (79%) were received. Of all 132 responses, the most frequent opinion expressed was that their acne was about the same (46%) compared with the previous week, followed by slightly improved (43%). The remaining responses were slightly worse (8%), significantly worse (2%) and significantly better (1%). Most participants expressed their satisfaction that their numbers of lesions had reduced during treatment and they did not have expectations that their acne would be completely gone at the end of the study. Tolerability No serious adverse events occurred. The highest score for any tolerability parameter was 3 (moderate), recorded at week 4 for three participants. One participant experienced moderate scaling, one moderate peeling and one moderate dryness. For the remaining weeks, scores ranged from 0 to 2. An additional participant reported a minor itch within the first few days of applying the product. Overall mean tolerability scores, calculated as the average of all values recorded for all six tolerability indicators were 0.89 at baseline, 0.73 at 4, 0.40 at 8 and 0.29 at 12 weeks, indicating that the treatment was well tolerated. Mean local tolerability scores calculated for the six individual tolerability parameters, as determined by the investigators at baseline, 4, 8 and 12 weeks, are shown in Figure 3. Erythema differed significantly from baseline at 8 and 12 weeks (P < 0.05) and peeling at 4 weeks differed significantly from 12 weeks (P < 0.01). Scaling differed significantly between weeks by ANOVA but post-hoc tests were not significant. There were no other significant differences. Figure 3 Mean tolerability scores for acne products containing tea tree oil applied to the face. Note that burning and induration were not recorded at baseline as the products had not been used. Erythema, scaling and peeling differed significantly by ANOVA.

Tea tree oil products for acne treatment 209 Product acceptability evaluation Product acceptability data was obtained from 15 participants, comprising 13 completed and two withdrawn participants. The questions pertained only to the gel and not the face wash. The highest score was 5 for strongly agree with the statement and the lowest was 1 for strongly disagree. Modal scores ranged from 3 to 5 and mean scores ranged from 3.5 to 4.6, indicating that overall the gel was well accepted. The lowest scores were for fragrance acceptability and ease of absorption while the highest scores were for texture, consistency and ease of application. DISCUSSION This pilot study showed that the use of a gel and face wash containing Australian tea tree oil significantly reduced numbers of acne lesions and was well tolerated. In addition, the products were highly acceptable to the participants. The efficacy may be due, in part, to antibacterial activity, given that both products were active against P. acnes in laboratory tests. It remains possible that study factors such as the gel base product, or the regular, structured facial care routine contributed to the improvement in acne. A phase III placebo-controlled and double-blinded study would be required to evaluate this possibility. Most previous studies evaluating tea tree oil for treating acne have assessed products containing 5% tea tree oil applied for 4 8 weeks. 13 16 In these studies mean reductions in total lesion counts ranged from 29% to 62%, with an average across studies of approximately 45%. 13 16 This is similar to the current study, which found a mean reduction in total lesion count of 54% at 12 weeks. It is difficult to compare this overall result with other topical treatments such as benzoyl peroxide or antibiotic creams but an evaluation of existing literature found comparable rates of efficacy. 17 20 For example, percentage changes in total lesion counts found for benzoyl peroxide ranged from 36% to 48% 18,20 and for clindamycin gel ranged from 31% to 47%. 17,21,22 However, the long-term use of antibiotics such as clindamycin and erythromycin, either topically or orally, is discouraged due to the development of resistance by P. acnes 23 and the potential spread of resistance determinants to other bacteria. As a result of antimicrobial resistance, the use of combination topical therapies, and of non-antibiotic products such as tea tree oil, has become highly relevant. The products evaluated in the current study were well tolerated, with no serious adverse events and only minor local tolerability events. The rate of adverse events was lower than in previous studies with tea tree oil products, 7 although the gel contained a higher concentration than those assessed previously. This may be due to differences in criteria for adverse events between studies or due to true differences between the tolerability of the products evaluated. A recent review of the efficacy and safety of tea tree oil products for treating acne 7 suggested that its efficacy is attributable to the antimicrobial and anti-inflammatory activity of tea tree oil. In theory, the antimicrobial activity acts against P. acnes, which is found in acne lesions, and the anti-inflammatory activity may inhibit both the inflammatory responses to P. acnes and the innate immune responses that are found in acne-prone skin. Additional mechanisms demonstrated for other acne treatment agents such as decreasing sebum production and normalising keratinisation have not been demonstrated for tea tree oil thus far. CONCLUSION These data support previous findings that tea tree oil products reduce numbers of lesions and are well tolerated when used for the treatment of mild to moderate facial acne. Further double blinded, controlled trials are necessary to thoroughly evaluate the efficacy and safety of tea tree oil products in patients with acne. ACKNOWLEDGEMENTS The authors thank Thursday Plantation (Integria Healthcare (Australia) Pty Ltd) for providing the study products. This study was supported Rural Industries Research and Development Corporation (PRJ-006245). REFERENCES 1. Kurokawa I, Danby FW, Ju Q et al. New developments in our understanding of acne pathogenesis and treatment. Exp. Dermatol. 2009; 18: 821 32. 2. Stathakis V, Kilkenny M, Marks R. Descriptive epidemiology of acne vulgaris in the community. Australas. J. Dermatol. 1997; 38: 115 23. 3. Holzmann R, Shakery K. Postadolescent acne in females. Skin Pharmacol. Physiol. 2014; 27(Suppl. 1): 3 8. 4. Misery L. 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