Abstract

Background: An effective patient-centered approach is essential for managing acne vulgaris, a commonly treated skin disease. While commercially available options include oral and/or topical preparations in fixed doses, compounded formulations allow the qualitative and quantitative composition to be personalized to each patient.
Objective: This study aimed to assess the effectiveness (or non-inferiority) and clinical acceptance of CleodermTM, a ready-to-use, semi-solid vehicle for acne treatment.
Methods: We performed an exploratory randomized, split-face, single-blind clinical trial of 10 patients with facial acne. Participants were randomly assigned to receive two treatments for four weeks, and the hemiface of each treatment was randomly specified. All treatments had the same active ingredients but different
Vehicles: a commercial base or CleodermTM, a ready-to-use vehicle for compounding pharmacies. Lesion counts and global acne severity ratings of bilateral patients’ photographs were performed. Sebum production was visually inspected, and patient self-assessment reports were conducted.
Results: The clinical assessment and bilateral facial photographs showed that baseline Leeds scores for all subjects were similar for all treatments. After four weeks, both sides were graded as slightly better. However, 80% of the subjects had better skin outcomes in the hemiface receiving treatment with CleodermTM compared to the hemiface treated with a commercial vehicle base.
Conclusion: Both subgroups treated with standard active pharmaceutical ingredients compounded in CleodermTM presented better treatment efficacy and less discomfort. This suggests that compounded topical formulations might be an excellent alternative to personalize acne treatment.

Introduction

Acne vulgaris is a chronic inflammatory dermatosis affecting the pilosebaceous follicles of the skin [1]. It is one of the most common skin disorders worldwide, impacting all age groups, independent of sex and ethnic background [2]. Its prevalence is around 85% in adolescents and young adults, and among adult women is around 12% [3,4]. Acne pathogenesis is multifactorial, involving sebum production, follicular hyperkeratinization, hypercolonization by Cutibacterium acnes, and complex inflammatory mechanisms [5]. Clinically, acne has a variable presentation, including open or closed comedones (blackheads and whiteheads) and inflammatory lesions, such as papules, pustules, nodules, or cysts [6]. In most patients, the face is affected, and the trunk may also be involved in up to 61% of cases [7]. Acne lesions can progress to scars and/or post-inflammatory hyperpigmentation which can have harmful physical and psychological consequences, including poor self-image, depression, and anxiety [8,9]. Given the high prevalence and impact on patients’ health-related quality of life, early treatment is important to optimize acne management [10,11]. Topical, oral, and physical therapies are available and may be influenced by the patient’s age, preferences, site of involvement, and disease severity [12]. Topical therapies may be used as monotherapy with other topical agents with oral agents.[5] Commonly used oral treatments include antibiotics, hormones, and isotretinoin. In contrast, topical ones can involve benzoyl peroxide, salicylic acid, retinoids, azelaic acid, and antibiotics [13-18]. In addition, previous studies showed that physical interventions, such as peeling and laser therapy, have also improved clinical outcomes [19].

Although various conventional therapies are available, the need for additional safe, convenient, and efficacious topical treatment options for acne remains [20,21]. Moreover, patient-centered acne management is crucial due to its varied presentations, chronicity, and impact on an individual’s well-being [12]. While commercial preparations are available in fixed doses, compounded formulations allow the qualitative and quantitative composition to be personalized to each patient [22]. Therefore, this study aimed at investigating the safety profile and clinical acceptance of CleodermTM, a ready-to-use, semi-solid vehicle for acne treatment [23].

Methods

Study Design

Study participants were recruited from a private dermatology clinic in Barcelona (Spain). The recruitment occurred between November and December 2022, and the study was completed in March 2023. Written informed consent was obtained from all study participants. Inclusion criteria were patients 13 years or older, from both sexes, with moderate to severe acne vulgaris based on physician clinical assessment (at least a Leeds acne severity scale rating of 2 on a 12-point ordinal scale), no chronic diseases or comorbidities, and ability to adhere to the study protocol. Exclusion criteria were age younger than 13 years, pregnancy, acne due to secondary causes, the presence of other dermatological diseases of the face, oral retinoid use within one year of study entry, microdermabrasion of the face within three months of study entry, alpha hydroxy acid, or glycolic acid use within one month of study entry, and a history of dermabrasion or laser resurfacing of the facial skin. Before the study entry, all participants were washed-out from systemic antibiotic use or anti-acne topical treatment for one month. The study was a randomized, split-face, single-blind clinical trial comparing four treatments. Participants were randomly assigned to receive two treatments, and the hemiface of each treatment was randomly specified. All treatments had the same concentration of the same active ingredient but different vehicles. Study participants received specific instructions regarding the treatments. In brief, the topical creams should be applied daily at night in a quantity of 1.0 fingertip units (FTU) (or 1.2 grams, to cover the entire hemiface). Treatments were conducted for four weeks by a dermatologist. Participants were clinically assessed at baseline and four weeks later (study endpoint). Evaluations included formal counts of papules, pustules, cysts, comedones, numbers of inflamed, noninflamed, total acne lesions on the face, and Michaelson’s acne severity score. In addition, a visual examination of sebum production levels was performed. Facial photographs were obtained from each participant’s face front and left, and right profile views. Photographs were taken using standardized studio lighting and subject positioning. Images were obtained at baseline and week 4.

These photographs were subsequently viewed by a dermatologist blinded to which side of the face each treatment was applied. The modified Leeds acne severity scale was used to grade the severity of acne demonstrated by each patient on each side of the face. Also, patients’ impressions of the treatment and the associated results regarding their acne severity and the degree of oiliness of their skin were considered at the end of the treatment phase. During the treatment phase of the study, all participants were instructed about diet, physical activity, and hygiene procedures. They were requested to follow a low-glycemic, junk/ processed/spicy food-free diet with skimmed milk. In addition, it was recommended to avoid strenuous activities, sun exposure, and stressful events. The hygiene instruction included washing their faces with regular soap and water only twice daily and after exercise.

Treatment groups

Study participants were randomly divided into two groups. Subjects in group 1 received adapalene 0.1% + benzoyl peroxide 2.5% in commercial vehicle base (treatment A) one-half of the face, with the contralateral face being treated with adapalene 0.1% + benzoyl peroxide 2.5% in Cleoderm ^TM (treatment B). Subjects in group 2 received erythromycin 0.3% + benzoyl peroxide 5.0% in commercial vehicle base (treatment C) to one-half of the face, with the contralateral face being treated with erythromycin 0.3% + peroxide benzoyl 5.0% in Cleoderm ^TM (treatment D).

Statistical analysis

For all endpoints, the change from baseline for the side treated with a commercial vehicle base was compared with the change from baseline for the side treated with Cleoderm^TM in all patients. The efficacy data (lesion counts, global acne severity rating, and sebum production) were visually inspected.

Results

Participant Characteristics

A total of 10 potential participants were screened; ten subjects met all eligibility criteria and were randomized (Figure 1). Five male and five female participants aged 14 to 17 were enrolled in the study. All participants had a European ethnic background and subscribed to the appropriate age educational level at school. Of all, 50% of the participants underwent treatment with Cleoderm^TM, and all participants completed the entire 4-week-long study.

Treatment group 1

In general, participants reported a decrease in acne severity and the degree of skin oiliness at the end of the study period in treatments A and B. The treatments were well tolerated, and no adverse reactions were reported. However, 80% of the study participants reported increased skin sensitization and discomfort in the hemiface receiving treatment A. The clinical assessment and bilateral facial photographs were performed by a dermatologist at baseline and week 4. Overall, all participants improved their skin outcomes with both treatments at the end of the study. However, in 80% of the study participants, the hemiface receiving treatment B had better outcomes than treatment A (Figure 2A,2B,2C,2D,2E).

Treatment group 2

Overall, participants reported a decrease in acne severity and the degree of oiliness of their skin in treatments C and D. The treatments were well tolerated, and no erythema, scaling, and dryness, along with burning or pruritus, were reported. However, 80% of the study participants reported increased mild skin discomfort in the hemiface receiving treatment C. The clinical assessment and bilateral facial photographs showed that baseline Leeds scores for all subjects were similar for treatments C and D. After four weeks, both sides were slightly better (Figure 3, 3A,3B,3C,3D). However, in 80% of the study participants, the hemiface receiving treatment D had better outcomes than treatment C. At the time points studied, no statistically significant differences were noted in sebum production when comparing both treatments.

Discussion

In this randomized, split-face, single-blind clinical trial, all participants showed slightly improved skin outcomes at the end of the treatment phase based on participants’ self-report and dermatologist clinical assessment. However, 80% of the subjects reported increased skin discomfort in the hemiface receiving treatments A and C (with commercial vehicles base), compared to the hemiface receiving treatment B and D, respectively. In addition, in 80% of the study participants, the hemiface receiving treatments B and D (with Cleoderm^TM) had better outcomes than those receiving treatments A and C.

Although adapalene, benzoyl peroxide, and erythromycin have shown clinical efficacy in previous studies, managing patients with acne remains challenging in daily clinical practice [13,17,18,24,25]. Adapalene is a topical retinoid that modulates epidermal growth and differentiation and stimulates humoral and cellular immunity, ideally decreasing cell proliferation and inflammatory response [18,24]. Benzoyl peroxide has bactericidal effects after skin absorption is converted to benzoic acid. In the skin, the residual benzoic acid is metabolized and releases active free-radical oxygen species resulting in the oxidization of bacterial proteins [13,24].

Erythromycin, a topical macrolide antibiotic, effectively reduces inflammatory acne lesions by decreasing the density of Cutibacterium acnes and directly inhibiting neutrophil chemotactic factors and reactive oxygen species production [3,17,25]. However, cutaneous side effects, including dryness, scaling, stinging/ burning, and erythema, have been reported to be associated with these active pharmaceutical ingredients [26,27]. Consequently, patients may exhibit poor adherence to their treatment, leading to inadequate treatment responses. In this context, the vehicle base can significantly influence treatment outcomes by improving efficacy and reducing side effects [28-30]. The vehicle base should promote the adequate percutaneous absorption of different active ingredients and avoid potentially irritating or allergenic components, such as petrolatum, mineral oils, lanolin, perfumes, polyethylene glycol, and fatty alcohols [31]. Therefore, the current study compared the effectiveness (or non-inferiority) and clinical acceptance of Cleoderm^TM, a ready-to-use compounded vehicle, to a commercial vehicle base. The results of this study suggest that CleodermTM might offer a gentler impact on the skin while serving as an adequate vehicle to enhance the efficacy of active ingredients and improve the overall appearance of the skin.

Limitations

This study has some limitations. As it is an exploratory study, the number of subjects and the quantitative parameters measures were limited. However, the results encourage our team to perform a larger clinical assessment.

Conclusion

Both subgroups treated with standard active pharmaceutical ingredients compounded in Cleoderm^TM presented better treatment efficacy and less discomfort. This suggests that compounded topical formulations might be an excellent alternative to personalizing acne treatment.

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