Acne RA‐1,2, a novel UV‐selective face cream for patients with acne: Efficacy and tolerability results of a randomized, placebo‐controlled clinical study

General skincare measures such as the use of moisturisers and products containing adequate photoprotection are important components of acne patients’ management to complement the pharmacological regimen. Acne RA‐1,2 is a novel dermato‐cosmetic product which contains selective photofilters and active ingredients against the multifactorial pathophysiology of acne.


| INTRODUCTION
Acne is a multifactorial disease of the pilosebaceous unit involving increased sebum production, altered keratinization, colonization by Propionibacterium acnes, and inflammation. 1 An effective acne treatment needs to address as many of these underlying disease factors as possible. In so doing, an optimal acne treatment would quickly reduce the clinical signs of acne and consequently the impairment to quality of life and psychosocial burden that this highly visible disease causes. 2 In addition to the use of pharmacological treatments for acne, there is increasing interest in the use of dermato-cosmetic products which can complement the medical regimen such as the use of moisturisers and products with adequate photoprotection. 3 These dermato-cosmetics can help to maintain the integrity of the stratum corneum and to reduce the local skin reactions caused by topical treatments such as retinoids and benzoyl peroxide (BPO). [3][4][5] They may also improve patients' adherence to their pharmacological acne treatment, which is estimated to be poor in 50% of patients. 6 Acne RA-1,2 is a new dermato-cosmetic product which was designed to provide selective protection from daily UV light, with additional clinical benefits for acne-prone and acne-affected skin.
This randomized, double-blind, placebo-controlled study was carried out to evaluate the effect of Acne RA-1,2 on the clinical signs of acne (number of comedones, transepidermal water loss [TEWL], and sebum production) as well as determining its tolerability. Patients did not use any pharmacological acne medications during this study.

| Patients
Patients were eligible for participation in this study if they were Caucasian adults aged at least 18 years with greasy facial skin and with 10-25 open and closed comedones per half face. Patients had to stop their pharmacological treatment for acne at least 4 weeks before the study start and had to agree not to expose themselves intensively to UV rays during the study. Patients were excluded if they received a systemic treatment for acne, and if pregnant or breastfeeding, if female. Patients were also excluded if they were taking food supplements which could interfere with the study medication, or if they had other skin conditions in the area to be treated.

| Evaluations
The effects of study treatments were evaluated after 4 and 8 weeks of their daily use.

| Statistical analyses
All statistical tests were carried out using NCSS 10-PROFES- vs the placebo group was compared using a Mann-Whitney U test.
TEWL and sebum production at Weeks 4 and 8 were compared to those at baseline using repeated-measures analysis of variance (ANOVA) followed by Tukey-Kramer post-test. These parameters were compared in the two treatment groups using a bilateral Student's t test for unpaired data.

| Patients
In total, 40 acne patients were enrolled into this study: 20 into the

| Clinical improvement in acne
There was a significant 35% reduction in the mean number of comedones in the Acne RA-1,2 group from 26 at baseline to 17 at Week

| TEWL and sebum production
Mean TEWL was significantly reduced by 7% from 9.32 g/h/m 2 at baseline to 8.66 g/h/m 2 after 8 weeks of Acne RA-1,2 treatment (P<.001; Figure 1B). Mean sebum production was significantly reduced by 24% from 154.8 lg/cm 2 at baseline to 117.6 lg/cm 2 after 8 weeks of Acne RA-1,2 treatment (P<.001; Figure 1C). Both TEWL and sebum production were significantly lower in the Acne RA-1,2 and placebo groups at Weeks 4 and 8.

| Patient evaluations
In the Acne RA-1,2 group, there was a 36% improvement in patient's rating of their acne from a mean of 5.3 at baseline to 3.4 after 8 weeks of treatment ( Figure 2). In contrast, in the placebo group, there was only a 12% improvement in patient's rating of their acne from a mean of 5.8 at baseline to 5.1 at Week 8 ( Figure 2). Two examples of the clinical improvement experienced by patients in the Acne RA-1,2 group are shown in Figure 3.

| Tolerability
There were no adverse events during the study.

| DISCUSSION
This is the first placebo-controlled study to evaluate the tolerability and effect of Acne RA-1,2 against the clinical signs of acne. The results of this study showed a significant reduction in comedones in the Acne RA-1,2 group compared with baseline as assessed by the investigators and a significant improvement in acne as evaluated by patients. Clinical improvements in epidermal barrier function and reduced sebum production were also observed. Furthermore, Acne RA-1,2 was shown to be noncomedogenic and well tolerated by patients with no adverse events occurring during the study. This is important, because to be appropriate for use in acne patients, dermato-cosmetic products must not lead to worsening of acne and must not irritate the already sensitive skin. 31 The efficacy of Acne RA-1,2 against acne reported in this study may be due to this treatment selectively filtering UV rays and due to its active ingredients which target several of the underlying components of the disease including P. acnes, inflammation, and sebum production ( Table 1). The selective photofilters present in Acne RA-1,2 provide protection against UVB rays and allow partial penetration of UVA rays around 400 nm in wavelength. UVB rays have multiple detrimental effects on acne such as inducing inflammation, [10][11][12][13] increasing proliferation of keratinocytes, 14 and increasing production of sebum. 15,16 In contrast, specific UVA wavelengths around 400 nm may have beneficial anti-inflammatory actions in both acne-prone and acne-affected skin. [7][8][9] Together, the components of Acne RA-1,2 led to a clinical improvement in the signs of acne and a reduction in the number of comedones in this study.
Acne RA-1,2 was associated with a significant improvement in epidermal barrier function in this study-as evidenced by a reduction in TEWL-compared with both baseline and placebo. This is important given that acne itself and many therapies used to treat acne (eg, topical retinoids and BPO) impair the stratum corneum, resulting in increased TEWL, skin sensitivity, and inflammation. 3 This study also demonstrated a significant reduction in sebum production with Acne RA-1,2 vs both baseline and placebo. Acne RA-1,2 contains the active ingredient, 1,2-decanediol, which has previously been shown to significantly reduce sebum levels by 20% in acne patients and so is most likely responsible for the reduction in sebum production observed with Acne RA-1,2 in the current study. 20,21 The reduced sebum production with Acne RA-1,2 is a unique and important feature of this dermato-cosmetic product given that no currently available pharmacological option for the topical treatment of acne is able to target this underlying pathogenic factor of acne.
In this study, patients in the placebo group experienced a significant reduction in comedones at Weeks 4 and 8 vs baseline, but no significant changes in TEWL or sebum production. All patients in the study were asked to clean their face every day with the same cleanser, and this may have contributed to the reduction in comedones in the placebo group.
The study was conducted in the autumn season of 2015. This season was selected because sebum production and skin moisture are higher in the autumn compared with other seasons. 33 Consequently, this provided us with the optimal opportunity for evaluating the effects of Acne RA-1,2 on these parameters. The summer season was avoided given that intense sun exposure, heat, humidity, and sweating can aggravate acne in a proportion of patients, whereas others experience an improvement in acne due to the camouflaging effect of tanning. 34 While UVA is present equally throughout daylight hours and seasons, UVB is strongest from April to October. Acne RA-1,2 provides an SPF of 30 (calculated based on UVB protection), which protects patients from normal daily light but not from sunburn. Consequently, the study was conducted outside the seasons of most intense UVB radiation, and patients were also advised to avoid intensive UV exposure during the study to avoid the negative effects that sunburn could have on acneic skin, which is more sensitive and inflamed than normal skin.
The results of this placebo-controlled study complement the data from a previously conducted real-life study in which the effects of Acne RA-1,2 were evaluated when added on to pharmacological acne treatment. 35 The previous study showed that Acne RA-1,2 significantly reduces the skin irritation that topical pharmacological acne treatments such as retinoids and BPO can cause. Acne RA-1,2 also led to a significant increase in adherence to pharmacological acne treatment, and similar to the results of the current study, the combined use of Acne RA-1,2 and pharmacological therapy led to a clinical improvement in acne and epidermal barrier function and a decrease in sebum production.
The main limitations of this placebo-controlled study were the small sample size and short duration of follow-up. The small sample size was considered appropriate for the initial evaluation of the safety and tolerability of Acne RA-1,2 in a randomized, placebo-controlled clinical trial. In the future, studies could assess the efficacy and tolerability of Acne RA-1,2 in larger placebo-controlled studies of longer duration both when used alone and in combination with pharmacological acne treatments. Another limitation was the inclusion of a population comprising mainly adult females with acne.
Given that adult female acne may have a different clinical presentation and pathogenesis to adolescent acne, 36 future studies should also evaluate Acne RA-1,2 in different populations including both adolescent and adult males and females.

| CONCLUSION S
Acne RA-1,2 was well tolerated and led to a significant reduction in comedones, a significant improvement in epidermal barrier function and a significant decrease in sebum production. These beneficial effects against the clinical signs of acne suggest that Acne RA-1,2 may be useful in patients with acne-prone facial skin as part of their daily skincare routine. The ability of Acne RA-1,2 to reduce sebum production is particularly noteworthy because this is not targeted by existing topical pharmacological acne treatments.

ACKNOWLEDG MENTS
This study was funded by Meda Pharma (a Mylan company). Medical writing assistance in the preparation of this manuscript was provided CESTONE ET AL.