In this clinical study, we conducted a 12‐week, single‐blind, randomized and split‐face comparative study of A‐BPO gel and BPO 2.5% in Korean acne patients, focusing on two clinical subjects. First, A‐BPO gel and BPO were compared for their efficacy and tolerability in Asian skin. Second, after all patients were further randomly assigned to dermatological tutorial (DT) and non‐tutorial (NT) subgroups based on the presence of dermatologists' tutorials for application methods to their A‐BPO side, clinical benefit of a dermatological tutorial on application technique in reducing local irritations for A‐BPO was assessed.

Physicians sometimes encounter a fair number of patients who prematurely discontinue topical acne medications due to local adverse effects. 7 Because both adapalene and benzoyl peroxide (BPO) may alter integrity of the skin barriers, the potential irritation effect of this combination gel could be problematic. 8 Compared with Caucasians, Asians have complained of irritations more often in previous studies of topical retinoid and clindamycin/BPO. 9 - 11 Because many of the reported side‐effects are attributable to poor application techniques, we hypothesized that a dermatological tutorial for demonstrating proper application methods with concomitant use of a non‐comedogenic moisturizer might reduce product‐related irritations, leading to improved patients' therapeutic adherence.

To clinically address the multifactorial pathogenesis of acne, a unique, fixed‐dose gel combining adapalene 0.1% and benzoyl peroxide 2.5% (A‐BPO) has emerged. The synergistic efficacies shown in previous studies 1 - 3 make this agent a rational primary choice in treating all but the severest forms of acne. With these efficacies, A‐BPO also has advantages in preventing selective pressure for resistance in Propionibacterium acnes as antibiotics do. 4 , 5 However, the majority of clinical trials conducted involved Caucasian populations, so data focusing on Asian patients only is sparse. Because structural and biophysical distinctions among ethnic skin types may exist, 6 potential differences in efficacy and tolerability are to be expected.

This clinical study was conducted in the outpatient dermatology clinic of Seoul National University Hospital between January 2014 and February 2015. It was determined that 65 subjects would confer more than 90% power to detect a 15% difference in success rates (defined below), assuming a standard deviation of 25%. To compensate for patient withdrawal, a total of 85 subjects were enrolled. At initial presentation, all patients received random assignments for their split‐face applications of either A‐BPO or BPO. A simple random allocation sequence was devised (a block size of four) and allocation was performed by a research nurse. The integrity of blinding was ensured by packaging the topical medications in identical tubes and requiring a third party to dispense them. Full clinical data between each half facial side for A‐BPO and BPO was compared (analysis I). At the initial assignment, patients were further randomly assigned in a similar manner to either one of two subgroups (DT or NT), whereby a dermatological tutorial for application method of A‐BPO was presented only for DT subgroup per visit. Clinical data between each half facial side for A‐BPO in DT and NT was compared (analysis II). After completion of assignments, they were asked to apply two topical agents once daily to all acne lesions of the assigned half side, respectively. Follow‐up evaluations were conducted at weeks 1, 2, 4, 8 and 12. Patient compliance was also monitored by phone periodically (three times/week). All enrolled patients were unaware of group assignments until the end of the study. The overall study flow is presented in Figure 1 .

The intent‐to‐treat (ITT) population included all randomly assigned subjects who were dispensed study medications. All ITT subjects adhering to protocol without any major deviations comprised the per protocol (PP) population. A last observation carried forward approach was applied to data generated by 15 dropouts. The Cochran–Mantel–Haenszel test was used to determine significance of proportionate success rates, as well as percent changes from baseline in acne lesion counts and value changes after device measurements. All statistical analysis relied on standard software (SPSS ver. 21.0; SPSS, Chicago, IL, USA), with significance set at P < 0.05.

To evaluate safety issues objectively, transepidermal water loss (TEWL), reflecting skin barrier function, was measured via open‐chamber evaporimeter (Tewameter; Courage & Khazaka, Cologne, Germany). Erythema was assessed by both erythema index (EI) of Dermaspectrometer (Cortex Technology, Hadsund, Denmark) and a* value (balance between red [positive value] and green [negative value] based on the L*a*b* system recommended by the Commission International de l'Eclairage) of Tristimulus colorimeter (Spectrophotometer CM‐2002; Minolta, Osaka, Japan). To quantify sebum output, sebumeter strips (Skin‐O‐Mat; Cosmomed, Wetter, Germany) were also applied for 30 s at least 6 h after washing the face with soap. Three measurements, taken from the glabella and both cheeks were averaged at each time point for respective measurements to minimize variations in rooms at constant temperature/humidity.

Overall acne severity grade based on PGA and counts of inflammatory and non‐inflammatory acne lesions were performed at each visit. Sequential bioengineering device measurements were also conducted accordingly. Success rate was defined as the percentage of facial sides rated “clear” and “almost clear” by PGA. To ensure reliability of evaluations, standardized digital photographs using identical camera settings (Nikon D70; Nikon, Tokyo, Japan) were taken. Subjective self‐assessments of patients on a scale from 0 (“complete improvement”) to 5 (“worst”) were also rated at week 12. For safety profiles, dermatologists rated erythema, scaling, dryness and stinging/burning of all patients using a scale of 0 (“none”) to 3 (“severe”) at each follow up.

Each half face of the 85 study participants was graded as 2–4 via Physician Global Assessment (PGA) scale (Table 1 ). Subjects were prohibited from using any systemic, topical or light‐based acne treatments during the course of study. Exclusion criteria included pregnancy, mental illness, oral isotretinoin intake within 6 months and use of other topical or oral acne medications, chemical peels or light‐based treatments within 6 weeks. Full demographic data is presented in Table 2 . The study was approved by the institutional review board of Seoul National University Hospital (Clinical Trials Registration no. NCT02192632) and conducted in accordance with the Declaration of Helsinki.

Tolerability parameters of adapalene 0.1% and benzoyl peroxide 2.5% gel (A‐BPO) application side in dermatological tutorial (DT) and non‐tutorial (NT) subgroups. (a) Erythema, (b) scaling, (c) dryness and (d) stinging/burning. Variables scored as follows: none, 0; mild, 1; moderate, 2; and severe, 3. Mean scores shown at each visit during treatments. *Baseline and therapeutic differences (A‐BPO or benzoyl peroxide [BPO], P < 0.05), † A‐BPO vs BPO ( P < 0.05).

Among all safety issues observed in the A‐BPO side, frequency and intensity of local adverse effects were significantly lower in the DT subgroup compared with NT subgroup. Overall proportions of subjects experiencing at least one adverse event related with therapy were 34.4% and 80.7% for DT and NT, respectively. Compared with the NT subgroup, all local irritations including erythema, scaling, dryness and stinging/burning scored significantly lower in the DT subgroup until follow up at week 12 (Fig. 6 ). After 1 week of application, mean total irritation scores (the sum of each four scores) peaked distinctly (DT, 1.9; NT, 5.4), falling significantly after 4 weeks in the DT (0.7) and 12 weeks in the NT (2.4) subgroup. Of 11 patients who withdrew due to local adverse effects (i.e. dry skin, scaling, erythema and stinging or burning sensations) in the A‐BPO side, the relative proportion was significantly lower in DT (4.7%, 2/42) compared with NT (20.9%, 9/43) subgroup assignees. Changing patterns of Tewameter and Dermaspectrometer readings of both subgroups were generally consistent with clinical data (data not shown).

The A‐BPO application side of both subgroups achieved comparable therapeutic success. Inflammatory and non‐inflammatory lesions declined in similar fashions (Fig. S1). In addition to objective measurements made at each follow‐up point, proportions of subjective self‐ratings indicating “complete improvement” or “marked improvement” in skin condition did not differ significantly (87.5% in DT and 83.4% in NT).

All enrolled patients were further assigned to either DT or NT subgroup. Only for the A‐BPO side of the DT subgroup patients, dermatologists with full information of specific assignments educated them in the application method each visit, emphasizing the importance of applying only a limited amount and to restricted areas during initial periods of use. Patients were also instructed to apply a non‐comedogenic moisturizer or skin lotion to the face approximately 10 min before applying A‐BPO gel (Fig. 5 ). Before the start of the study, we carefully explained the definition of “non‐comedogenic moisturizer” to the patients in detail. Then, patients were advised to bring their moisturizers and dermatologists confirmed their compositions.

Mean changes in biophysical skin parameters by (a) Tewameter (transepidermal water loss, TEWL), (b) Dermaspectrometer (EI), (c) Spectrophotometer and (d) Sebumeter during the whole study period. *Baseline and therapeutic differences at each visit (adapalene 0.1% and benzoyl peroxide 2.5% gel [A‐BPO] or benzoyl peroxide [BPO], P < 0.05), † A‐BPO vs BPO ( P < 0.05).

To assess local irritation effects of topical agents objectively, degrees of skin barrier disruption and inflammation‐related erythema were measured by bioengineering devices (Fig. 4 a–c). TEWL peaked at week 1 (A‐BPO, 41.9; BPO, 35.2) and steadily declined through week 12 (A‐BPO, 29.9; BPO, 25.4). Erythema also peaked at week 1 (EI; A‐BPO, 25.3; BPO, 22.0 and a*; A‐BPO, 11.2; BPO, 9.3) and declined at week 12 (EI; A‐BPO, 19.3; BPO, 18.7 and a*; A‐BPO, 9.3; BPO, 8.9), consistent with changes of safety profiles during clinical course. For measuring sebum production, only A‐BPO sides demonstrated significant decreases at week 12 compared with baseline ( Fig. 4 d).

Tolerability parameters in adapalene 0.1% and benzoyl peroxide 2.5% gel (A‐BPO) and benzoyl peroxide (BPO) sides. (a) Erythema, (b) scaling, (c) dryness and (d) stinging/burning. Variables are scored as follows: none, 0; mild, 1; moderate, 2; and severe, 3. Mean scores are shown at each visit during treatments. *Baseline and therapeutic differences at each visit (A‐BPO or BPO, P < 0.05), † A‐BPO vs BPO ( P < 0.05).

For the entire time window of study, both frequency and intensity of local irritation effects were more severe in A‐BPO‐treated sides, compared with BPO sides. In the A‐BPO sides, 63.3% experienced at least one treatment‐related adverse event compared with 50.0% of facial sides using BPO only. The most frequently reported adverse event after 1 week was dry skin (53.3%), followed by scaling (46.7%), erythema (40.0%) and stinging or burning sensations (40.0%). Average scores of erythema, scaling, dryness and stinging/burning sensations at each follow up were higher for A‐BPO compared with baseline throughout the 12‐week period (Fig. 3 ). After 1 week of topical use, mean irritation scores peaked for both regimens with significant between‐group differences recorded for all parameters except dryness. The average sum of these four irritation scores declined significantly after 8 weeks of A‐BPO (1.8) and 4 weeks in BPO (1.2) compared with week 1 data of each regimen (3.4 in A‐BPO, 2.3 in BPO). All adverse events were dermatological in nature and resolved completely with no residual effects.

Clinical efficacy parameters in adapalene 0.1% and benzoyl peroxide 2.5% gel (A‐BPO) and benzoyl peroxide (BPO) sides. (a) Success rates, median percentile changes from baseline in (b) inflammatory and (c) non‐inflammatory lesions during clinical trial, and (d) respective proportions of subjective patient self‐assessments at week 12. *Baseline and therapeutic differences at each visit (A‐BPO or BPO, P < 0.05), † A‐BPO vs BPO ( P < 0.05).

In evaluating success rates, defined as percentages of facial sides rated as “clear” or “almost clear” on PGA, A‐BPO gel (78.2%) proved superior to BPO (45.5%) at week 12. Significant early treatment effect was observed with A‐BPO compared with BPO, commencing at week 1 and persisting through study completion (Fig. 2 a). Similarly, percentile changes from baseline in counts of inflammatory (A‐BPO, 79.8%; BPO, 63.1%) and non‐inflammatory (A‐BPO, 68.8%; BPO, 57.8%) lesions confirmed a superior response for A‐BPO at week 12 (Fig. 2 b,c). Patients' subjective assessments were generally consistent with those of objective evaluations. Percentages of facial sides indicating “complete improvement” or “marked improvement” were 85.5% for A‐BPO and 61.8% for BPO at week 12 (Fig. 2 d). End‐point analysis was repeated for the PP population to confirm ITT efficacy outcomes.

A total of 85 subjects were initially enrolled, constituting the ITT population. Overall, 70 patients (82.4%) completed the study (PP population). Two patients withdrew for personal reasons, 11 patients for skin irritations on the A‐BPO side and two on the BPO side.

Discussion

Fixed‐dose A‐BPO combination therapy is widely prescribed for acne and well acknowledged as a highly effective approach for treating this complex skin disease. Although the superior efficacy of A‐BPO has been underscored by a few clinical trials,1, 2, 13 most of them were conducted in Western countries and independent data for Asian patients only is quite rare. The current study generally confirmed synergistic actions of A‐BPO in Asian acne patients, based on all enhanced efficacy parameters beyond those achieved with BPO alone. Even compared with large‐scale studies of Caucasian populations, the extent of resolution seen in non‐inflammatory and inflammatory acne lesions alike was at least comparable or somewhat higher for Korean patients despite slight differences in study designs. Onset of action was also equivalent or faster than that documented by Western data.

Although some earlier studies have shown that adapalene may be added to other therapies without significantly aggravating skin irritations,14, 15 our research clearly demonstrated that local cutaneous adverse effects of BPO were heightened significantly in frequency and intensity by adding adapalene to the formulation. Furthermore, our tolerability profiles for A‐BPO registered a much higher frequency of irritations even compared with that encountered in Western populations,2, 3, 16 in contrast with a previous report indicating no proclivity to such irritations depending on Fitzpatrick skin types.17 Objective measurements of skin barrier disruption and inflammation‐induced erythema during initial application periods substantiated our clinical findings as well. While controversies still exist regarding ethnic differences in skin sensitivity, increased susceptibility to irritations has been noted by previous reports when applying topical anti‐acne agents to Asian patients.9-11 Asian skin has also proved more sensitive to stripping than Caucasian skin,18 with easily altered barrier function of the stratum corneum by external stimuli. Korean dermatologists often experience that maintaining patients' adherence to prescribed topical anti‐acne agents was sometimes quite challenging.

Because most adverse effects typically occur during the early phase in this type of treatment, we hypothesized that a dermatological tutorial, instructing patients on application techniques and focusing on the importance of product adaptation, may encourage consistent use of A‐BPO.

Frequency and intensity of the major adverse cutaneous effects declined significantly in a better educated patient subgroup (DT); and drop‐out rates due to local adverse effects was also much lower in facial sides of patients counseled enough on product use. Controlling the amount and the area of gel application during the initial utilization period may help to gradually acclimatize skin to the combination gel. Moreover, concomitant use of a non‐comedogenic moisturizer may also aid in preserving the protective barrier effect of skin. A few groups have equally claimed that instructions on skin care by dermatologists would enhance therapeutic adherence and quality of life for acne patients.19, 20 Indeed, a combination of oral and written forms may be also effective for educating patients as in our cases.22, 23 Considering the greater vulnerability but higher response potential of Asian skin to A‐BPO gel, incorporating dermatological tutorials into patient management with emphasis on concomitant moisturizer use would be sure to improve compliance and adherence in Korean patients.

Several aspects of this study need further mention. First, direct comparison between Asian and Western acne population under completely the same study protocol might have produced more valid data. Second, more frequent evaluations during the first week of application would have provided detailed information about skin adverse effects during the early phase.

In conclusion, A‐BPO demonstrated higher efficacies in acne compared with BPO in Korean patients, while skin irritation levels were notable concurrently. Dermatologists' education for application methods with use of non‐comedogenic moisturizers would significantly decrease these side‐effects, maintaining superior efficacy levels.