doi: 10.1111/j.1346-8138.2011.01450.

Journal of Dermatology 2012; 39: 511515

ORIGINAL ARTICLE

Multicenter randomized controlled trial on combination therapy with 0.1% adapalene gel and oral antibiotics for acne vulgaris: Comparison of the efcacy of adapalene gel alone and in combination with oral faropenem
Nobukazu HAYASHI,1 Makoto KAWASHIMA2
1 Department of Dermatology, Toranomon Hospital, and 2Department of Dermatology, Tokyo Womens Medical University, Tokyo, Japan

ABSTRACT
We conducted a randomized controlled trial in patients with acne vulgaris with moderate to severe inammatory lesions. The patients were assigned to the following three treatment groups: group A received monotherapy with 0.1% topical adapalene gel for 4 weeks; group B received combination therapy with 0.1% topical adapalene gel and 600 mg oral faropenem for 2 weeks followed by 0.1% topical adapalene gel alone for 2 weeks; and group C received combination therapy with 0.1% topical adapalene gel and 600 mg oral faropenem for 4 weeks. The result of the analysis indicated that the percentage reduction in inammatory lesion counts after 2 weeks of treatment was signicantly higher in groups B and C than in group A (P < 0.05). After 4 weeks of treatment, group C showed signicantly higher percentage reduction in inammatory lesion counts than in groups A and B (P < 0.05), whereas no signicant difference was noted between the latter two groups. Adverse reactions included dryness and irritation at the adapalene application sites that were observed in 10.1% of cases (16 158 patients) and diarrhea and loose stool because of oral faropenem that were observed in 7.5% of cases (8 106 patients). Taken together, our results suggest that combination therapy with oral antibiotics and adapalene results in earlier improvement in patients with moderate to severe inammatory acne compared to the application of adapalene alone, and that 4 weeks of the combination therapy is preferable to 2 weeks of treatment.

Key words: acne vulgaris, adapalene, combination therapy, faropenem, oral antibiotics, randomized controlled trial.

INTRODUCTION
The guideline for the treatment of acne vulgaris published by the Japanese Dermatological Association1 (hereafter referred to as the Guideline) strongly recommends the combination use of 0.1% adapalene gel (hereafter referred to as adapalene) and oral antibiotics for treating patients with moderate to severe inammatory acne (recommendation level A). This recommendation has been made on the basis of the results of clinical trials comparing the efcacy of oral tetracyclines alone and in combination with adapalene.2,3 However, the effects of adding oral antibiotics to adapalene have not been investigated, and there has been no report indicating the suitable duration of combination therapy. Faropenem, an oral b-lactam penem antibacterial agent, has been approved for treating acne in Japan; it shows excellent efcacy on inammatory acne.46 The effects of faropenem on inammatory acne are not signicantly different from those of mino-

cycline, a tetracycline antibiotic, and roxithromycin, a macrolide antibiotic.4 Faropenem has a highly potent antibacterial activity against Propionibacterium acnes,4,6 and administration of the agent for 4 weeks does not lead to drug resistance.4 The present study aimed to determine the effects of combination therapy with adapalene and oral antibiotics and the preferable duration of the therapy.

METHODS
Study design
Between February and September 2010, a multicenter, open-label, randomized parallel-group controlled trial was conducted at 25 dermatological institutions (Fig. 1). This study was reviewed and approved by the Institutional Review Board of Mizuo Clinic and was conducted in accordance with the ethical guidelines established by the Declaration of Helsinki

Correspondence: Nobukazu Hayashi, M.D., Ph.D., Department of Dermatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku 105-8470, Tokyo, Japan. Email: hayashi@toranomon.gr.jp Conict of interest: This study was nancially supported by a non-prot organization, the Health Institute Research of Skin. Received 27 September 2011; accepted 17 October 2011.

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All patients were asked to wash their faces and apply adapalene to the entire face before bedtime once daily for 4 weeks. The moisturizers were used before the application of adapalene. The patients in groups B and C were administrated 200 mg faropenem p.o. three times daily for 2 and 4 weeks, respectively.

Concomitant drugs and therapy

Concomitant use of drugs indicated for acne, other drugs and therapy that may have an inuence on acne, or cosmetic products expected to relieve acne were prohibited during the study period. However, p.o. administration of antibiotics (except azithromycin) for 3 days or less for accidental mild complications to protect patients health; topical application of non-comedogenic moisturizers; and use of vitamin B2, B6, C and E preparations were permitted. Hormone therapy and physical treatments were prohibited.

Figure 1. Study protocol. All patients applied topical adapalene gel once-daily for 4 weeks. Group A, monotherapy with adapalene gel; group B, combination of adapalene gel with faropenem for 2 weeks; group C, combination of adapalene gel with faropenem for 4 weeks.

Evaluation methods
Clinical efcacy The number of inammatory lesions (sum of papules and pustules) and non-inammatory lesions (comedones) on the entire face were counted at the initiation of the study, and at 1, 2 and 4 weeks after the initiation. The percentage reduction in inammatory lesion counts calculated by comparing the counts at each observation point versus baseline levels was regarded as the primary end-point. Changes in inammatory and non-inammatory lesion counts were considered as secondary end-points. Safety assessment When any adverse events were observed during the study period, the symptoms or name of the disease, date of onset, implementation of treatment and its content, and outcome were recorded. Adverse events that might have causal relationships with the study drugs were regarded as adverse reactions. Quality of life survey At the initiation of the study, and at 2 and 4 weeks after the initiation, the quality of life (QOL) of acne patients was surveyed using the Japanese version of Skindex-16,8 a QOL scale specic to patients with skin diseases. Skindex-16 scores were calculated as previously described.8

and the Ethical Guideline for Clinical Research (fully revised on 31 July 2008, Ministry of Health, Labor and Welfare). After explaining all of the protocols, written informed consent was obtained from each patient who participated in this study. If the patient was under 20 years old, consent was obtained from a legal guardian.

Subjects
Patients who were 16 years or older and had moderate to severe acne vulgaris according to the severity grading criteria established by the Japanese Acne Study Group7 (Table 1) were enrolled. Patients were excluded on the basis of the following criteria: (i) patients who had received drugs indicated for acne vulgaris (oral, topical or injectable) within the past 4 weeks; (ii) patients with a history of hypersensitivity to the study drugs; (iii) patients who were continuously using non-steroidal anti-inammatory drugs; (iv) patients who were or may have been pregnant or were breastfeeding; and (v) patients judged as ineligible by the attending physician.

Method of administration
At the initiation of the study, patients were randomly assigned to the three groups by using the envelope method, and the study drugs were administrated to groups AC as follows: (A) monotherapy with topical adapalene for 4 weeks; (B) combination therapy with topical adapalene and oral faropenem for 2 weeks followed by topical adapalene alone for 2 weeks; and (C) combination therapy with topical adapalene and oral faropenem for 4 weeks. Table 1. Severity grading criteria (Acne Study Group)7 Severity Mild Moderate Severe Very severe Inammatory lesion counts per half face 05 620 2150 >50

Analysis methods
Statistical analysis was performed using JMP ver. 9.0 software. With regard to percentage reduction in inammatory and noninammatory lesion counts, the Wilcoxon rank sum test was used to analyze signicant differences between the three treatment groups. The Wilcoxon signed rank test was used to analyze signicant differences between the baseline and each observation point. In regard to Skindex-16 scores, one-way ANOVA was used to compare between the treatment groups, and a paired Students t-test was used to compare between the baseline and each observation point. The v2-test was used to analyze incidence rates of adverse reactions in each treatment group. The two-sided signicance level was set at less than 5% (P < 0.05).

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RESULTS
Composition of enrolled patients and patient proles
Compositions of the 160 enrolled patients (group A, n = 52; group B, n = 56; group C, n = 52) are shown in Figure 2. Two patients who did not return to the test centers after the initial consultation were excluded from safety analysis, and nine patients were excluded from efcacy analysis due to discontinuation caused by adverse events, and protocol violations for severity and age as well as pregnancy after enrollment. In all, 158 and 149 patients were enrolled in the safety analysis and efcacy analysis, respectively. The patient who became pregnant after enrollment showed no abnormality at delivery; the baby was also normal. Patient proles for the 149 patients in the efcacy analysis (group A, n = 49; group B, n = 48; group C, n = 52) are shown in Table 2. No obvious bias was found between the three groups with respect to patient proles such as sex, age, duration of disease, severity, and inammatory and non-inammatory lesion counts.

Table 2. Patient proles No. of patients (n = 149) Patient proles A B C 52

Clinical efcacy
Figure 3(a) shows the percentage reduction in inammatory lesion counts (median values), which was the primary end-point, at each observation point. While the percentage reduction after 2 weeks of treatment was 31.6% in group A, the values were 48.7% and 56.4% in groups B and C, respectively. A signicant difference was observed between group A and groups B and C (P < 0.05). The percentage reduction in inammatory lesion counts after 4 weeks of treatment was 44.5% in group A, 46.7% in group B and 63.3% in group C. Signicant differences were observed between groups A and C and between groups B and C (P < 0.05), whereas no signicant difference was observed between group A and group B (P 0.05). However, there were no signicant differences in the percentage reduction of non-inammatory lesion counts between the three groups (Fig. 3b). Inammatory and non-inammatory lesion counts, as secondary end-points, were signicantly reduced

No. of subjects 49 48 analyzed Sex Male 15 17 Female 34 31 Age (years) Mean 22.4 24.7 SD (min, max) 5.0 (16, 37) 6.2 (16, 40) Duration of disease (month) Mean 45.7 36.6 SD (min, max) 42.7 (0, 172) 49.8 (0, 254) History Yes 6 4 No 43 44 Complication Yes 7 11 No 42 37 Concomitant drugs Yes 21 29 No 28 19 Severity of acne vulgaris Moderate 45 46 Severe 4 2 Inammatory lesion counts at baseline Median (min, max) 17.0 (8, 67) 19.0 (9, 67) Non-inammatory lesion counts at baseline Median (min, max) 20.0 (3, 102) 18.0 (3, 156)

15 37 24.9 6.1 (16, 41) 47.4 60.2 (1, 253) 3 49 12 40 26 26 44 8 18.0 (8, 60) 18.0 (1, 103)

Group A, monotherapy with adapalene gel; group B, adapalene gel plus faropenem for 2 weeks; group C, adapalene gel plus faropenem for 4 weeks. SD, standard deviation.

in all three groups at all observation points after 1 week of treatment compared with those at baseline (P < 0.05) (data not shown).

Safety
During the study period, adverse reactions that may have been related to adapalene, included dry skin, contact dermatitis, erythema, swelling, skin irritation, skin burning sensation and desquamation; these adverse reactions were observed in 10.1% of cases (16 158 patients). Two patients in group A discontinued the study due to an adverse reaction caused by adapalene. Adverse reactions related to faropenem included diarrhea, loose stool and malaise; these were observed in 7.5% of cases (8 106 patients) (Table 3). Four of them were prescribed antibiotic-resistant lactic acid bacteriae. All eight patients completed their protocol. No signicant differences were observed between each group with respect to incidence rates of adverse reactions (P 0.05).

QOL assessment
Quality of life assessment results based on the Japanese version of Skindex-16 (symptoms, emotions and functioning scale scores and total scores) are shown in Figure 4. In all the groups, the emotions and functioning scale scores and the total scores signicantly decreased after 2 and 4 weeks of treatment compared with those

Figure 2. Subjects analyzed. Group A, monotherapy with adapalene gel; group B, adapalene gel plus faropenem for 2 weeks; group C, adapalene gel plus faropenem for 4 weeks.

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(a)

(a)

(b)

(b)

(c)

(d)

Figure 3. Percentage reduction in inammatory lesion counts (a) and percentage reduction in non-inammatory lesion counts (b). *P < 0.05, **P < 0.01, Wilcoxon rank sum test. Group A, monotherapy with adapalene gel; group B, adapalene gel plus faropenem for 2 weeks; group C, adapalene gel plus faropenem for 4 weeks. Table 3. Treatment-related adverse events
Adapalene-related adverse events No. of Treatment patients (rate) group A (n = 52) 5 (9.6%) Symptoms (no. of cases) Faropenem-related adverse events No. of patients Symptoms (rate) (no. of cases)

Figure 4. Evaluation of the quality of life based on Skindex-16 (Japanese version). No signicant differences were observed between the three groups with regard to the scores for symptoms (a), emotions (b) or functioning (c) scales, or for total scores (d), at any observation time (one-way ANOVA). *P < 0.05, **P < 0.01, ***P < 0.001 paired Students t-test (vs baseline). Values represent mean standard error of the mean (SEM). Group A, monotherapy with adapalene gel; group B, adapalene gel plus faropenem for 2 weeks; group C, adapalene gel plus faropenem for 4 weeks. at baseline (P < 0.05). The symptoms scale scores signicantly decreased only after 4 weeks of treatment in group C compared with those at baseline (P < 0.05). No signicant differences in any of the scores were observed between the three groups (P 0.05).

Dry skin (3) Contact dermatitis (2) Erythema (1) Swelling (1) B (n = 54) 6 (11.1%) Dry skin (6)* 4 (7.4%) Diarrhea loose Erythema (1) stool (4)* Skin irritation (1) Desquamation (1) C (n = 52) 5 (9.6%) Dry skin (5)* 4 (7.7%) Diarrhea loose Erythema (1) stool (4)* Skin burning Malaise (1) sensation (1) Total 16 (10.1%) 8 (7.5%)
*Both adapalene-related dry skin and faropenem-related diarrhea were observed in three patients; two patients of group B, and one patient of group C. Group A, monotherapy with adapalene gel; group B, adapalene gel plus faropenem for 2 weeks; group C, adapalene gel plus faropenem for 4 weeks.

DISCUSSION
Although the percentage reduction in inammatory lesion counts after 4 weeks of treatment was 44.5% in group A, the percentage reduction after 2 weeks reached 48.7% and 56.4% in groups B and C, respectively. Compared with adapalene monotherapy, combination therapy with adapalene and faropenem decreased the time required to reduce inammatory lesions by half. Improvement of inammatory lesions is necessary for patients to become aware of overall relief of symptoms; early onset of therapeutic effects is important for enhancement of patient adherence. In regard to safety, all adverse reactions were mild and caused no serious problem. Thus, we propose that oral antibiotics should be used concomitantly with adapalene to achieve better and earlier effects in acne patients with moderate to severe lesions. Our results suggested that 4 weeks and not 2 weeks of combination therapy with adapalene and faropenem was adequate for

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treatment of moderate to severe inammatory acne. In a randomized controlled trial comparing minocycline, roxithromycin and faropenem that were administrated p.o. for 4 weeks followed by 4 weeks of follow-up observation, inammatory lesion counts were reduced by approximately 60% after 4 weeks of treatment with the oral antibiotics, and their therapeutic effects on inammatory lesions were maintained for 4 weeks after the completion of the treatment.4 Thiboutot et al.9 suggest that whether the treatment with oral antibiotics needs to be discontinued should be decided during 612 weeks after treatment initiation. However, our results suggest that this decision should be made on the fourth week after treatment initiation in consideration of factors such as the therapeutic effects, treatment progress and patient proles. The QOL assessment showed no signicant differences in any of the scores between the three groups. However, the emotions and functioning scale scores and the total scores signicantly decreased after 2 and 4 weeks of treatment compared with those at baseline in all groups, and the QOL was improved. The symptom scale scores were signicantly decreased only after 4 weeks of treatment in group C compared with those at baseline. Because the combination therapy with adapalene and faropenem for 4 weeks produced better therapeutic effects on inammatory lesions, the therapy may have exerted a benecial inuence on the QOL. The results of this study revealed better and earlier effects of combination therapy with adapalene and oral antibiotics. They supported the Japanese Guideline1 that strongly recommends combination therapy with adapalene and oral antibiotics for treating moderate to severe acne (recommendation level A). Two weeks administration of oral antibiotics with adapalene brought earlier improvement of inammatory lesions. However, a duration of 4 weeks was suggested to be necessary for achieving better outcomes with the combination therapy.

Mita Dermatology Clinic; Yasuhiro Kawabata, Kawabata Dermatology Clinic; Rika Kikuchi, Miyabayashi Clinic; Hiroto Kitahara, Kitahara Dermatology Clinic; Ataru Matsukawa, Kura Dermatology and Plastic Surgery Clinic; Jun Mayama, Chitose Dermatology and Plastic Surgery Clinic; Reiko Morikawa, Junko Nakagawa, Megumino Dermatology Clinic; Tomoko Murata, Tsubasa Clinic; Osamu Nemoto, Kenji Saga, Kuniko Kawamura, Sapporo Dermatology Clinic; Mariko Ooe, Murahashi Medical Clinic; Emiko Sawamura, Emiko Dermatology Clinic; Mariko Tochiki, Kitamatsudo Dermatology Clinic; Koki Tomizawa, Nopporo Dermatology Clinic; Haruyoshi Yamada, Yamada Dermatology Clinic; Mina Yamada, Yotsuya-Sanchome Skin Care Clinic; Hidemi Yasuda, Fukuzumi Dermatology Clinic; Mihoko Yokoyama, Yokoyama Skin Clinic. (Alphabetical arrangement, honorics omitted.)

REFERENCES
1 Hayashi N, Akamatsu H, Iwatsuki K et al. The guideline for the treatment of acne vulgaris. Jpn J Dermatol 2008; 118: 18931923 (in Japanese). 2 Cunliffe WJ, Meynadier J, Alirezai M et al. Is combined oral and topical therapy better than oral therapy alone in patients with moderate to moderately severe acne vulgaris? A comparison of the efcacy and safety of lymecycline plus adapalene gel 0.1%, versus lymecycline plus gel vehicle J Am Acad Dermatol 2003; 49: S218S226. 3 Thiboutot DM, Shalita AR, Yamauchi PS, Dawson C, Arsonnaud S, Kang S. Combination therapy with adapalene gel 0.1% and doxycycline for severe acne vulgaris: a multicenter, investigator-blind, randomized, controlled study. Skinmed 2005; 4: 138146. 4 Hayashi N, Kawashima M. Efcacy of oral antibiotics on acne vulgaris and their effects on quality of life: a multicenter randomized controlled trial using minocycline, roxithromycin and faropenem. J Dermatol 2011; 38: 111 119. 5 Nogita T. Clinical efcacy of faropenem sodium (FRPM) in the treatment of acne vulgaris with inammatory lesions. J New Rem & Clin 2008; 57: 511 518 (in Japanese). 6 Endo H, Wada T, Narita T et al. Clinical study of faropenem (FRPM) for acne vulgaris with inammatory lesions: antibacterial activities of various antibacterial agents on Propionibacterium acnes and Staphylococcus epidermidis isolated from patients with acne vulgaris. Antibiot Chemother 2009; 25: 95102, (in Japanese). 7 Hayashi N, Akamatsu H, Kawashima M. Acne Study Group, establishment of grading criteria for acne severity. J Dermatol 2008; 35: 255260. 8 Higaki Y, Kawamoto K, Kamo T, Horikawa N, Kawashima M, Chren MM. The Japanese version of Skindex-16: a brief quality-of-life measure for patients with skin diseases. J Dermatol 2002; 29: 693698. 9 Thiboutot D, Gollnick H, Bettoli V. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol 2009; 60: S1S50.

ACKNOWLEDGMENTS
We are extremely grateful to attending physicians at the medical institutions listed below for participating in the conduct of this study. Drs Toshiya Asai, Asai Dermatology Clinic; Hiroyuki Asanuma, Takashi Onozuka, Yumiko Koike, Asanuma Dermatology Clinic; Mami Chiba, Iderea Skin Clinic Daikanyama; Eiji Dobashi, Dobashi Dermatology Clinic; Toshiya Ebata, Chitofuna Dermatology Clinic; Hidenori Fukunaka, Fukunaka Dermatology Clinic; Shohei Futaki, Futaki Skin Care Clinic; Mieko Hata, Sakiko Kato, Takano Medical Clinic; Hiroki Kanda,

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