Evaluation of the efficacy of maintenance therapy for acne vulgaris using adapalene 0.1%/benzoyl peroxide 2.5% gel and benzoyl peroxide 2.5% gel for 24 weeks and assessment of atrophic acne scars using three‐dimensional image analysis

Maintenance therapy after remission of inflammation is strongly recommended in the guideline for the treatment of acne vulgaris published by the Japanese Dermatological Association. One advantage of continuing maintenance therapy is the alleviation of atrophic scarring. This study investigated the efficacy of maintenance therapy using adapalene 0.1%/benzoyl peroxide 2.5% gel and benzoyl peroxide 2.5% gel, and its effects on atrophic scarring. Overall, 126 patients were randomized to the adapalene/benzoyl peroxide group (n = 40), benzoyl peroxide group (n = 44), and control group (without maintenance treatment drugs; n = 42), and 111 of these completed a trial lasting 24 weeks. As the primary endpoint, the treatment success rate (the percentage of patients in whom the number of inflammatory lesions was maintained at ≤10) was 89.2% in the adapalene/benzoyl peroxide group, 87.5% in the benzoyl peroxide group, and 47.4% in the control group. Compared with the control group, the success rates were significantly higher in the adapalene/benzoyl peroxide and benzoyl peroxide groups (P = 0.0006 for both). As one of the secondary endpoints, the rate of change in the number of atrophic scars showed significant improvement from the baseline in the adapalene/benzoyl peroxide and benzoyl peroxide groups at week 24 (P = 0.0004 and P < 0.0001, respectively). Although the three‐dimensional image analysis parameters did not change significantly from the baseline in the adapalene/benzoyl peroxide and benzoyl peroxide groups at week 24, significant worsening was noted in the control group (P = 0.0276 for affected area, P = 0.0445 for volume, and P = 0.0182 for maximum depth). Adverse drug reactions were noted in three patients in the adapalene/benzoyl peroxide group (7.5%) but not in the benzoyl peroxide group. These findings suggest that maintenance therapy using adapalene 0.1%/benzoyl peroxide 2.5% gel and benzoyl peroxide 2.5% gel is effective in preventing the worsening of scars in Japanese patients with acne vulgaris.


| INTRODUC TI ON
Acne vulgaris is a chronic inflammatory disease that develops in pilosebaceous glands in the face and the thoracodorsal region.
One goal of acne treatment is to prevent atrophic scarring.Even mild acne can leave scars, with one report stating that atrophic scars, including mini scars, were observed in 61.2% of patients with acne vulgaris. 1Such scarring is feared to negatively impact the quality of life of the patient.
Fixed combination of adapalene (ADP) 0.1%/benzoyl peroxide (BPO) 2.5% gel (ADP/BPO gel) has direct antibacterial and comedolytic effects, which are mediated by the ability of ADP to suppress the differentiation of epidermal keratinocytes and inflammation and the oxidation ability of BPO.The Guidelines for the Treatment of Acne Vulgaris (2017) published by the Japanese Dermatological Association (JDA guideline 2017) strongly recommend ADP 0.1% gel, BPO 2.5% gel (BPO gel), and ADP/BPO gel for treating inflammatory lesions in the acute inflammatory phase, followed by maintenance therapy after the remission of inflammation. 2Dreno et al. demonstrated that patients treated with ADP/BPO gel for 6 months exhibited a decreased risk of atrophic scarring and an improvement in the severity of acne scars. 3is result suggests that continuing ADP/BPO gel treatment even after remission in inflammatory lesions may contribute to preventing and alleviating acne scars.Recently, new objective methods for evaluating atrophic scars have been reported, including a quantitative evaluation method using a three-dimensional (3D) imaging system 4 and 3D image analysis (ANTERA 3D: Miravex Limited, Ireland). 5ile ADP/BPO gel and BPO gel are expected to play a vital role in treating patients with acne vulgaris, evidence is scarce on the efficacy of maintenance therapy for Japanese patients with acne vulgaris in actual clinical practice.Furthermore, how maintenance therapy affects atrophic scarring has not been completely elucidated.This study aimed to evaluate the efficacy of maintenance therapy with ADP/BPO gel and BPO gel and its effects on atrophic scarring using 3D image analysis.

| Patients
This study involved adult (≥20 years of age) patients diagnosed with acne vulgaris whose number of inflammatory lesions decreased to ≤10 during the acute-inflammatory-phase treatment within 3 months before consent was obtained and who had ≥10 and <100 atrophic scars (≥0.5 mm in diameter).Before enrollment, an investigator explained to each patient the plan of the study using explanatory text and obtained consent from the patient personally for participation in the study.
The exclusion criteria were as follows: 1. Patients who received oral administration of tranilast within 3 months before giving consent.
2. Patients with a previous history of hypersensitivity to the components of either ADP or BPO.
3. Patients who were pregnant, suspected to be pregnant, or breastfeeding.
4. Patients who wished to become pregnant during the study period.

Patients whose enrollment was deemed inappropriate by either
an investigator or a subinvestigator.
6. Patients who were enrolled in other clinical trials or studies for other antiacne drugs within 6 months before giving consent.

| Study design, treatments, and blinding
This multicenter, open, randomized, intergroup comparison study (Figure 1) was conducted at 13 medical institutions in Japan from August 31, 2020 to September 18, 2021 (Supporting Information Table S1).The subjects were enrolled and allocated using an electronic data capture (EDC) system.The allocation was performed dynamically (minimization method) at a ratio of ADP/BPO gel:BPO gel:control, the group without maintenance treatment drugs, of 1:1:1.
The allocation adjustment factor was the acute-inflammatory-phase F I G U R E 1 Study design.With the acute-inflammatory-phase drugs used as the allocation adjustment factor, the subjects were dynamically allocated (minimization method) at a ratio of 1:1:1 for the respective groups.In the ADP/BPO gel group and BPO gel group, increased application was allowed.In all groups, the concomitant use of moisturizer was permitted.Topical or oral antimicrobial drugs was permitted only if symptoms worsened in all groups.However, topical drugs containing ADP or BPO were prohibited in the control group.ADP, adapalene; BPO, benzoyl peroxide; ADP/BPO gel, adapalene 0.1%/benzoyl peroxide 2.5% gel; BPO gel, BPO 2.5% gel.drugs, which were the drugs primarily used during 3 months of treatment for the acute inflammatory phase and were classified into (1)   treatment including a combination of ADP and BPO, (2) treatment including BPO, (3) treatment including ADP, and (4) other treatments.
The investigators administered the respective drugs to the subjects allocated to the ADP/BPO gel and BPO gel groups for 24 weeks from the start date.Each subject applied a prescribed dose of the study drug to the affected site once daily after washing their face before going to bed as per the investigator's instructions.The patients in the control group were not treated with maintenance therapy drugs.In all groups, the subjects also used a moisturizing agent as necessary as per the investigator's instructions.If the symptoms worsened (if the number of inflammatory lesions exceeded 11 on the entire face), the investigator administered a topical or oral antimicrobial drug and the subject applied or ingested a prescribed dose as per the investigator's instructions.Administration of the following drugs, therapies, etc., was prohibited during the study period: 1. Drugs that may affect the evaluation of atrophic scars, such as oral tranilast.

Nonstudy drugs (drugs other than ADP/BPO gel and BPO gel)
with antiacne effects (However, the use of antimicrobial drugs was permitted if the symptoms of acne vulgaris worsened.Use was also permitted for diseases such as bacterial infection within 7 days.If an antimicrobial drug was used, the intended use, name, dose, and dosing period were entered in the EDC).
3. Quasi-drugs, cosmetics, etc., that may affect the efficacy evaluation for acne. 5. Quasi-drugs and cosmetics with no past record of use (except moisturizing agents).

Preparations containing ADP or BPO (only for the control group).
Prior to the implementation of this study, the principal investigator explained that the study would be implemented as per the protocol and that the patients would be fully informed using explanatory text, etc., thereby gaining approval from the Certified Clinical Trials Review Board (Osaka Medical and Pharmaceutical University, approval no.CRB5180010) and the administrators of the participating institutions.Before starting the study, the principal investigator submitted the implementation protocol to the Minister of Health, Labor, and Welfare and published it in the Japan Registry of Clinical Trials (jRCT No. jRCTs051200035, https://jrct.niph.go.jp/).This study was performed in accordance with the ethical principles of the Declaration of Helsinki, Clinical Trials Act, Enforcement Regulations on the Clinical Trials Act, and Act on the Protection of Personal Information.

| Efficacy outcomes
The primary endpoint was the success rate of the treatment (the percentage of patients in whom the number of inflammatory lesions on the entire face was maintained at ≤10 during the observation period).
The investigator confirmed the number of inflammatory lesions (sum of red papules and pustules) at the start of the study and at 4, 8, 12, 16, 20, and 24 weeks (on withdrawal) after the start of the study.
The secondary endpoints were as follows: (1)   S2): 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe.AN-TERA 3D images were captured using an ANTERA 3D camera at the start of the study and at 12 and 24 weeks (on withdrawal) after the start of the study to evaluate the changes in the shapes of atrophic scars.The anonymized data collected using the ANTERA 3D camera were compiled by Nikoderm Research Inc.The ANTERA 3D image sites (evaluation sites) were the right and left cheek regions.The analysis was performed using a large filter (the default filter capable of measuring depressions ≤3 mm in diameter).The means of the right and left sites were adopted as the parameter values.The evaluation sites were set to include at least one atrophic scar ≥0.5 mm in diameter.The evaluation area was 3.5 × 3.5 cm 2 in each cheek region.

| Safety outcomes
The safety evaluation items were (1) the occurrence rate of adverse events and (2) local irritation.The occurrences of adverse events were monitored from the start of the study through the end of the observation period or withdrawal.
Local irritation concerning erythema, desquamation, skin dryness, itchiness, and stabbing/burning sensations was evaluated on a four-point scale (0, none; 1, mild; 2, moderate; 3, severe) at the start of the study and at 4, 8, 12, 16, 20, and 24 weeks (on withdrawal) after the start of the study.

| Statistical methods
No previous studies have used the same primary endpoint as that used in this study.This study was aimed at exploratory evaluation, and it was difficult to provide statistical rationales for setting the target sample size.Accordingly, the study was designed to enroll a total of 120 patients (40 in each group) to allow data collection during the enrollment period.
As the primary endpoint, the success rate of the treatment (the percentage of patients in whom the number of inflammatory lesions on the entire face was maintained at ≤10 during the observation period) was analyzed in the full analysis set (FAS), and the rate and the 95% confidence interval (CI) were calculated for each allocation group.Moreover, a logistic regression analysis that included the allocation groups and the acute-inflammatory-phase drugs as models was performed to calculate the odds ratio with the control group, 95% CI, and P value.Furthermore, multiplicity was adjusted using Dunnett's test, and the results were treated as the primary analysis results.Likewise, the per-protocol set (PPS) (the population that complied with the implementation protocol) was analyzed to ascertain the robustness of the results.
As secondary endpoints, changes in the lesion count (inflammatory, noninflammatory, and total lesions), atrophic scar count, and the ANTERA 3D parameters (affected area, volume, and maximum depth) were analyzed.The summary statistics (the number of cases, mean value, standard deviation, minimum value, quartile point, and maximum value) were calculated for the actual measurement in each allocation group at each observation point.Moreover, the summary statistics (the number of cases, mean value, standard deviation, minimum value, quartile point, and maximum value) were calculated for the amount and rate of change from the baseline at the start of the study, and the P values were calculated using the Wilcoxon signedrank test.Furthermore, the actual measurement, amount of change, and the rate of change were compared with those in the control group, and the P values were calculated using the Wilcoxon rank sum test.In the analysis of the duration of use of the topical or oral antimicrobial drugs, the summary statistics (the number of cases, mean value, standard deviation, minimum value, quartile point, and maximum value) were calculated in each group and compared with those in the control group; the P values were calculated using the Wilcoxon rank sum test.In the analysis of the severity of acne scars (GSAAS), the summary statistics (the number of cases, mean value, standard deviation, minimum value, quartile point, and maximum value) were calculated for the actual measurement in each allocation group at each observation point and were compared with those in the control group; the P values were calculated using the Wilcoxon rank sum test.The significance level was set at 5%. completed the study and eight were withdrawn (five at the request of the subjects and three by the decision of the investigator).Among those who were withdrawn, we defined patients who had >10 inflammatory lesions on their faces at any time point as treatment-failure cases and included them in the analysis.In the control group, 38 subjects, including four withdrawn subjects satisfying the definition of treatment-failure cases, were evaluated in the efficacy analysis.

| Patients
Of the 126 subjects enrolled in this study, noncompliance with the implementation protocol was noted in 11 subjects.All these cases, which mostly comprised the concomitant use of prohibited drugs administration of antimicrobial drugs) in the control group, were reported as serious cases of noncompliance.
Table 1 shows the background of the subjects on consent acquisition.Although there were no major intergroup biases, the male ratio was low in the ADP/BPO gel group and there were no subjects with severe condition at the time of initial examination.Regarding the usage status of the study drugs, >70% of the subjects had a usage rate of ≥75% in both the ADP/BPO gel and BPO gel groups.3).Compared with the control group, the treatment success rates in the ADP/BPO gel and BPO gel groups were significantly higher (P = 0.0006 and P = 0.0006, respectively).In the PPS, the treatment success rate [95% CI] (number of subjects) was 93.3% [77.9, 99.2] (28/30 subjects) in the ADP/BPO gel group, 88.9% [73.9, 96.9] (32/36 subjects) in the BPO gel group, and 53.8% [33.4,73.4] (14/26 subjects) in the control group.Compared with the control group, the treatment success rates in the ADP/BPO gel and BPO gel groups were significantly higher (P = 0.0078 and P = 0.0080, respectively), which confirmed the robustness of the results.

| Changes in the lesion count
Supporting Information Tables S3-S5 list the changes in the lesion count.
At week 24, the number of inflammatory lesions was significantly smaller in both the ADP/BPO gel and BPO gel groups than in the control group (P = 0.0016 and P = 0.0482, respectively).
Significant differences were noted in the number of noninflammatory lesions at week 24 in both the ADP/BPO gel and BPO gel groups compared with the control group (P = 0.0055 and P = 0.0265, respectively).The number of total lesions at week 24 varied significantly from that in the control group in both the ADP/BPO gel and BPO gel groups (P = 0.0002 and P = 0.0061, respectively).

| Rate of change in the lesion count
Figure 4 shows the alterations in the rate of change in the lesion count.Significant differences were noted in the rate of change in the inflammatory lesion count at all observation points between the ADP/BPO gel and control groups.Between the BPO gel group and the control group, significant differences were observed at the observation points other than weeks 8 and 24.
Compared with the control group, the rate of change in the noninflammatory lesion count was significantly different in the ADP/ BPO gel group at observation points other than week 4.In the BPO gel group, significant differences were noted at observation points other than week 24.
The rate of change in the total lesion count in the ADP/BPO gel group was significantly different from that in the control group at all observation points.In the BPO gel group, significant differences were noted at observation points other than week 24.

| The duration of use of the topical or oral antimicrobial drugs
The number of subjects who used either topical or oral antimicrobial drugs during the study period was 4/40 in the ADP/BPO gel group,   The rate of change in the atrophic scar count over the 24 weeks was significantly different in both the ADP/BPO gel and BPO gel groups compared with the control group (P = 0.0016 and P = 0.0004, respectively).

| Changes in the severity of acne scars (GSAAS)
Supporting Information Figure S1 shows the changes in the severity of acne scars.
Compared with the control group, both ADP/BPO gel and BPO gel groups did not exhibit any significant differences at week 24 (P = 0.2546 and P = 0.6012, respectively).

F I G U R E 3
Treatment success rate (the percentage of patients in whom the number of inflammatory lesions was maintained at ≤10).A logistic regression analysis that included the allocation groups and the acute-inflammatoryphase drugs as models was performed to calculate odds ratios with the control group, 95% confidence intervals, and P values.Furthermore, multiplicity was adjusted using Dunnett's test.The 95% confidence interval was calculated using the Clopper-Pearson test.ADP/BPO gel, adapalene 0.1%/benzoyl peroxide 2.5% gel; BPO gel, BPO 2.5% gel.(P = 0.0182 vs baseline) in the control group.Thus, a significant increase was observed in the control group.

| Occurrence of adverse events
Adverse events, excluding irritative symptoms on the application site, occurred in five patients (12.5%) in the ADP/BPO gel group, 11 patients (25.0%) in the BPO gel group, and seven patients (16.7%) in the control group.Serious adverse events did not occur in the ADP/BPO gel and control groups, whereas one patient (2.3%) developed infectious mononucleosis in the BPO gel group.Adverse reactions occurred in three patients (7.5%) in the ADP/BPO gel group (one case of contact dermatitis [2.5%], one case of eczema [2.5%], and one case of erythema [2.5%]).No adverse reactions were observed in the BPO gel group.

| Local irritation evaluation
Supporting Information Figure S2 shows the results of local irritation evaluation.
The occurrences of local irritation (erythema, desquamation, skin dryness, itchiness, and stabbing/burning sensations) observed at week 0 decreased over time, with no noticeable signs of aggravation.

| DISCUSS ION
This study was conducted at 13 medical institutions in Japan and included 126 patients with acne vulgaris to evaluate the efficacy of maintenance therapy using ADP/BPO gel and BPO gel, and its effect on atrophic scarring.Approximately twice as many subjects were withdrawn in the control group compared with the ADP/BPO gel and BPO gel groups.
More than half of the withdrawn subjects in the control group were withdrawn at the request of the subjects themselves.Most subjects were withdrawn in the control group because the symptoms tended to worsen in this group owing to the lack of access to the maintenance therapy drugs.
As the primary endpoint, the treatment success rate was significantly higher in the ADP/BPO gel and BPO gel groups than in the control group.Not only were the subjects able to maintain the number of inflammatory lesions at ≤10 on the entire face but also the number of inflammatory lesions was reduced from the baseline.In However, in the maintenance phase where the number of inflammatory lesions in the entire face falls below 10, it would be beneficial for the patient to use BPO, which has no known resistant bacteria and possesses antimicrobial properties, as part of maintenance therapy.
One goal of this study was to evaluate the effects of continued maintenance on atrophic scarring.The investigators conducted an objective evaluation using 3D image analysis.The rate of change in the atrophic scar count between the baseline and week 24 significantly decreased in the ADP/BPO gel and BPO gel groups, whereas no changes were noted in the control group.
Compared with the control group, significant differences in the rate of change in the atrophic scar count were noted at week 24 in both the ADP/BPO gel and BPO gel groups.However, the severity of acne scars (GSAAS) in the ADP/BPO gel and BPO gel groups at week 24 was not significantly different from that in the control group.As an objective evaluation, significant differences in the rates of change in the 3D image analysis parameters (affected area, volume, and maximum depth) were noted only in the control group between the baseline and week 24.Specifically, this result suggests that while atrophic scars worsened in the control group, the subjects in the ADP/BPO gel and BPO gel groups did not experience aggravation.However, the improvement from baseline in the ADP/BPO gel and BPO gel groups at week 24 differed from that in the control group.Meanwhile, the rate of change in the atrophic scar count was significantly decreased in the treatment groups, the 3D image analysis parameters excluding the maximum depth in the ADP/BOP gel group tended to decrease without increasing, and the rate of change in the atrophic scar count and the 3D image analysis parameters tended to be similar.In addition, the evaluation included the total number of atrophic scars on the entire face and the 3D image analysis parameters in the right and left cheek regions (3.5 × 3.5 cm 2 ), and the difference in the range of evaluation was remission in this study.As previously mentioned, the results of the evaluation of the atrophic scar count and the objective evaluation using 3D image analysis were consistent in that maintenance therapy prevented the worsening of scars in the ADP/BPO gel and BPO gel groups.

Dreno et al. previously conducted a clinical study involving
patients with moderate or severe acne vulgaris and reported that the use of ADP/BPO gel in the acute-phase treatment did not increase atrophic scars and that the severity of acne scars improved 6 months later compared with the control group. 3Meanwhile, the present study confirmed that the use of ADP/BPO gel and BPO gel was associated with a decrease in atrophic scar counts and did not affect the alterations in the area, volume, and maximum depth of atrophic scars.When treatment with ADP/ F I G U R E 7 ANTERA 3D case images and changes in the parameters.(a) A case in the ADP/BPO gel group and (b) a case in the BPO gel group.The sites to be imaged using ANTERA 3D (evaluation sites) were the right and left cheeks.Large filters (the default filter capable of measuring depressions with a diameter of ≤3 mm) were used for analyses, and the green zone in the figures was detected as an atrophic scar and calculated as a parameter.The yellow zone denotes an unfurrowed indentation that was not detected by large filters as an atrophic scar.ADP/BPO gel, adapalene 0.1%/benzoyl peroxide 2.5% gel; BPO gel, BPO 2.5% gel; max, maximum.
BPO gel and BPO gel was continued even after the inflammatory lesions had subsided, scars were prevented from worsening.Although how BPO gel affects atrophic scars in the acute phase is unclear, the results reported by Dreno et al. and the findings of this study indicate that the continued use of ADP/BPO gel and BPO gel from the acute phase to the maintenance phase may prevent atrophic scars from increasing or worsening and may contribute to the prevention of atrophic scarring, which is one of the therapeutic goals.
To summarize the relationship between inflammatory lesions and atrophic scars, prevention of inflammatory lesions via maintenance therapy in the ADP/BPO gel and BPO gel groups may suppress the worsening of atrophic scars.These findings may serve as new therapeutic evidence in maintenance therapy using ADP/BPO gel and BPO gel, and may be useful in daily medical practice.
Adverse reactions occurred in three subjects (7.5%) in the ADP/ BPO gel group (one case of contact dermatitis [2.5%], one case of eczema [2.5%], and one case of erythema [2.5%]).None were observed in the BPO gel group.In the local irritation evaluation, the occurrences of local irritation (erythema, desquamation, skin dryness, itchiness, and stabbing/burning sensations) that were noted at week 0 decreased over time, with no noticeable signs of aggravation.
Thus, no major safety concerns were raised.
The above findings suggest that maintenance therapy using ADP/BPO gel and BPO gel may be effective in preventing the relapse of inflammatory lesions in Japanese patients with acne vulgaris.Furthermore, the objective evaluation of acne scars has revealed that the therapy reduced atrophic scars without aggravating them.
This work was an exploratory study that involved a small sample size (126 subjects).As the regions, institutions, and patient populations were limited in this study, its results may not be generalized, therefore future research should involve more institutions and patients.Finally, it should be noted that many of the subjects were wearing face masks during the study because the study period coincided with the COVID-19 pandemic.

ACK N OWLED G M ENTS
We extend our gratitude to EPS Corporation and Nikoderm Research Inc. for supporting our study.We thank Crimson Interactive Pvt. Ltd. (Ulatus; www.ulatus.jp)for their assistance in manuscript translation and editing.

FU N D I N G I N FO R M ATI O N
The study was supported by Maruho (Grant Number: EPI-401).
changes in the lesion count (inflammatory lesions, noninflammatory lesions, and total lesions); (2) the duration of use of the topical or oral antimicrobial drugs; (3) changes in atrophic scar count; (4) changes in the severity of acne scars (Global Severity of Atrophic Acne Scar [GSAAS]); and (5) changes in the ANTERA 3D parameters (affected area [mm 2 ], volume [mm 3 ], and maximum depth [mm]).The confirmation of the number of noninflammatory lesions (sum of closed comedones and open comedones) coincided with the confirmation of the number of inflammatory lesions.The number of acne scars (atrophic scars) was counted at the start of the study and 12 and 24 weeks (on withdrawal) after the start of the study.The severity of acne scars was evaluated at the start of the study and at 12 and 24 weeks (on withdrawal) after the start of the study on a five-point scale as per GSAAS (Supporting Information Table

Figure 2
Figure 2 shows the breakdown of the subjects.Overall, 126 patients consented to participate in this study.All patients allocated to the groups were enrolled in the safety analysis and maximum efficacy analysis populations.Of the 40 subjects in the ADP/BPO gel group, 37 completed the study and three were withdrawn (one at the request of the subject, one owing to an occurrence of adverse events [contact dermatitis], and one by the decision of the investigator).Of the 44 subjects in the BPO gel group, 40 completed the study and four were withdrawn (two at the request of the subjects and two by the decision of the investigator).Of the 42 subjects in the control group, 34

3 /
44 in the BPO gel group, and 22/42 in the control group (including 11 who received prophylactic administration).The duration of use of topical or oral antimicrobial drugs (median [minimum, maximum]) was 0 [0, 127] days in the ADP/BPO gel group, 0 [0, 28] days in the BPO gel group, and 5.5 [0, 176] days in the control group.

Figures 6
Figures 6 and 7 and Supporting Information Tables S6-S8 show the rate of change in the ANTERA 3D parameters (affected area,
this study, patients were administered topical or oral antimicrobial drugs if they had ≥11 inflammatory lesions on their faces.Compared to the findings in the control group, the duration of antimicrobial drug administration was shorter in the ADP/BPO gel and BPO gel groups, and the number of patients who received antimicrobial therapy was lower in these groups.The additional administration of antimicrobial drugs can affect the number of inflammatory lesions, total number of lesions, and evaluation of atrophic scars in the ADP/BPO gel and BPO gel groups; however, the evaluation including cases of treatment failure was considered reasonable owing to the treatment used in medical practice.Given that the control group included only 11 patients who concomitantly received prohibited antimicrobial drugs before the aggravation of symptoms, intergroup differences in the duration of administration might have been overrepresented.Nevertheless, we concluded that administering antimicrobial drugs in the control group increased the treatment success rate and did not affect the interpretation of the treatment success rate results.Drug susceptibility testing of antimicrobials against Cutibacterium acnes strains isolated from patients with acne has showed increased resistance rates against roxithromycin and clindamycin (27.4% and 20.7%, respectively).6From the perspective of addressing antimicrobial resistance, the JDA guideline 2017 asserted that maintenance therapy and antimicrobial treatment should be further optimized to avoid the emergence of drug-resistant bacteria and that the treatment standards should be further improved.In this study, maintenance F I G U R E 5 Rate of change in atrophic scar count (median).*P < 0.05 (vs baseline) calculated using the Wilcoxon signedrank test.ADP/BPO gel, adapalene 0.1%/ benzoyl peroxide 2.5% gel; BPO gel, BPO 2.5% gel.F I G U R E 6Rate of change in the ANTERA 3D parameters (median): (a) affected area, (b) volume and (c) maximum depth.*P < 0.05 (vs baseline) calculated using the Wilcoxon signed-rank test.ADP/BPO gel, adapalene 0.1%/benzoyl peroxide 2.5% gel; BPO gel, BPO 2.5% gel.therapy using ADP/BPO gel and BPO gel was effective in preventing the increase in the number of inflammatory lesions in many patients.In daily medical practice, administering antimicrobial drugs in the acute inflammatory phase is strongly recommended in JDA guideline 2017.1 In the FAS, the treatment success rate [95% CI] (number of subjects) was 89.2% [74.6, 97.0] (33/37 subjects) in the ADP/BPO gel group, 87.5% [73.2, 95.8] (35/40 subjects) in the BPO gel group, and 47.4% [31.0, 64.2] (18/38 subjects) in the control group (Fig-

TA B L E 1
Patient baseline demographics and clinical characteristics.
This study was funded by Maruho.H.T. received speaker fees, research funding, and fees for arranging education from Maruho.N.H. received speaker fees, consultancy fees, research funding, and fees for arranging education from Maruho.M.A. received speaker fees, consultancy fees, and research funding from Maruho.