doi: 10.1111/j.1346-8138.2011.01450.x Journal of Dermatology 2012; 39: 511–515

ORIGINAL ARTICLE

Multicenter randomized controlled trial on combinationtherapy with 0.1% adapalene gel and oral antibiotics for acnevulgaris: Comparison of the efficacy of adapalene gel aloneand in combination with oral faropenem

Nobukazu HAYASHI,1 Makoto KAWASHIMA2

1Department of Dermatology, Toranomon Hospital, and 2Department of Dermatology, Tokyo Women’s Medical University, Tokyo,

Japan

ABSTRACT

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We conducted a randomized controlled trial in patients with acne vulgaris with moderate to severe inflammatory 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 inflammatory lesion counts after 2 weeks of treatment was significantly higher in groups B

and C than in group A (P < 0.05). After 4 weeks of treatment, group C showed significantly higher percentage reduction in

inflammatory lesion counts than in groups A and B (P < 0.05), whereas no significant 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 adapa-

lene results in earlier improvement in patients with moderate to severe inflammatory 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 anti-

biotics for treating patients with moderate to severe inflammatory

acne (recommendation level A). This recommendation has been

made on the basis of the results of clinical trials comparing the

efficacy of oral tetracyclines alone and in combination with adapa-

lene.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

efficacy on inflammatory acne.4–6 The effects of faropenem on

inflammatory acne are not significantly different from those of mino-

orrespondence: Nobukazu Hayashi, M.D., Ph.D., Department of Dermat

okyo, Japan. Email: hayashi@toranomon.gr.jp

onflict of interest: This study was financially supported by a non-profit org

eceived 27 September 2011; accepted 17 October 2011.

2011 Japanese Dermatological Association

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 designBetween February and September 2010, a multicenter, open-label,

randomized parallel-group controlled trial was conducted at 25 der-

matological 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

ology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku 105-8470,

anization, the Health Institute Research of Skin.

511

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 for2 weeks; group C, combination of adapalene gel with faropenem for

4 weeks.

N. Hayashi and M. Kawashima

and the ‘‘Ethical Guideline for Clinical Research’’ (fully revised on

31 July 2008, Ministry of Health, Labor and Welfare). After explain-

ing 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.

SubjectsPatients 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-inflammatory drugs;

(iv) patients who were or may have been pregnant or were breast-

feeding; and (v) patients judged as ineligible by the attending

physician.

Method of administrationAt 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 A–C 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

SeverityInflammatory lesioncounts per half face

Mild 0–5Moderate 6–20

Severe 21–50

Very severe >50

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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 mois-

turizers 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 therapyConcomitant use of drugs indicated for acne, other drugs and ther-

apy that may have an influence 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.

Evaluation methods

Clinical efficacyThe number of inflammatory lesions (sum of papules and pustules)

and non-inflammatory 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 inflammatory lesion counts calcu-

lated by comparing the counts at each observation point versus

baseline levels was regarded as the primary end-point. Changes in

inflammatory and non-inflammatory lesion counts were considered

as secondary end-points.

Safety assessmentWhen any adverse events were observed during the study period,

the symptoms or name of the disease, date of onset, implementa-

tion 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 surveyAt 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 specific to patients

with skin diseases. Skindex-16 scores were calculated as previ-

ously described.8

Analysis methodsStatistical analysis was performed using JMP ver. 9.0 software.

With regard to percentage reduction in inflammatory and non-

inflammatory lesion counts, the Wilcoxon rank sum test was used

to analyze significant differences between the three treatment

groups. The Wilcoxon signed rank test was used to analyze signifi-

cant differences between the baseline and each observation point.

In regard to Skindex-16 scores, one-way ANOVA was used to com-

pare between the treatment groups, and a paired Student’s 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 significance level

was set at less than 5% (P < 0.05).

� 2011 Japanese Dermatological Association

Table 2. Patient profiles

Patient profiles

No. of patients (n = 149)

A B C

No. of subjects

analyzed

49 48 52

Sex

Male 15 17 15

Female 34 31 37

Age (years)Mean 22.4 24.7 24.9

SD (min, max) 5.0 (16, 37) 6.2 (16, 40) 6.1 (16, 41)

Duration of disease (month)

Mean 45.7 36.6 47.4SD (min, max) 42.7 (0, 172) 49.8 (0, 254) 60.2 (1, 253)

History

Yes 6 4 3No 43 44 49

Complication

Yes 7 11 12

No 42 37 40Concomitant drugs

Yes 21 29 26

No 28 19 26

Severity of acne vulgarisModerate 45 46 44

Severe 4 2 8

Inflammatory lesion counts at baseline

Median (min, max) 17.0 (8, 67) 19.0 (9, 67) 18.0 (8, 60)Non-inflammatory lesion counts at baseline

Median (min, max) 20.0 (3, 102) 18.0 (3, 156) 18.0 (1, 103)

Group A, monotherapy with adapalene gel; group B, adapalene gel plusfaropenem for 2 weeks; group C, adapalene gel plus faropenem for4 weeks. SD, standard deviation.

Combination adapalene ⁄ faropenem for acne

RESULTS

Composition of enrolled patients and patientprofilesCompositions 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 efficacy 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 efficacy analysis, respectively.

The patient who became pregnant after enrollment showed no

abnormality at delivery; the baby was also normal.

Patient profiles for the 149 patients in the efficacy 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 profiles such as sex, age, duration of disease, severity,

and inflammatory and non-inflammatory lesion counts.

Clinical efficacyFigure 3(a) shows the percentage reduction in inflammatory 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 significant difference was

observed between group A and groups B and C (P < 0.05).

The percentage reduction in inflammatory lesion counts after

4 weeks of treatment was 44.5% in group A, 46.7% in group B and

63.3% in group C. Significant differences were observed between

groups A and C and between groups B and C (P < 0.05), whereas

no significant difference was observed between group A and group

B (P ‡ 0.05). However, there were no significant differences in the

percentage reduction of non-inflammatory lesion counts between

the three groups (Fig. 3b). Inflammatory and non-inflammatory

lesion counts, as secondary end-points, were significantly reduced

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.

� 2011 Japanese Dermatological Association

in all three groups at all observation points after 1 week of treatment

compared with those at baseline (P < 0.05) (data not shown).

SafetyDuring the study period, adverse reactions that may have been

related to adapalene, included dry skin, contact dermatitis, ery-

thema, swelling, skin irritation, skin burning sensation and desqua-

mation; 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 bac-

teriae. All eight patients completed their protocol. No significant

differences were observed between each group with respect to

incidence rates of adverse reactions (P ‡ 0.05).

QOL assessmentQuality 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 significantly

decreased after 2 and 4 weeks of treatment compared with those

513

(a)

(b)

Figure 3. Percentage reduction in inflammatory lesion counts (a)

and percentage reduction in non-inflammatory lesion counts (b).

*P < 0.05, **P < 0.01, Wilcoxon rank sum test. Group A, monothera-py 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

Treatment

group

Adapalene-related

adverse events

Faropenem-related

adverse events

No. of

patients

(rate)

Symptoms

(no. of cases)

No. of

patients

(rate)

Symptoms

(no. of cases)

A (n = 52) 5 (9.6%) Dry skin (3)

Contact

dermatitis (2)

Erythema (1)

Swelling (1)

B (n = 54) 6 (11.1%) Dry skin (6)*

Erythema (1)

Skin irritation (1)

Desquamation (1)

4 (7.4%) Diarrhea ⁄ loose

stool (4)*

C (n = 52) 5 (9.6%) Dry skin (5)*

Erythema (1)

Skin burning

sensation (1)

4 (7.7%) Diarrhea ⁄ loose

stool (4)*

Malaise (1)

Total 16 (10.1%) 8 (7.5%)

*Both adapalene-related dry skin and faropenem-related diarrhea wereobserved in three patients; two patients of group B, and one patientof group C. Group A, monotherapy with adapalene gel; group B,adapalene gel plus faropenem for 2 weeks; group C, adapalene gelplus faropenem for 4 weeks.

(a) (b)

(c) (d)

Figure 4. Evaluation of the quality of life based on Skindex-16 (Japa-nese version). No significant 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 Student’st-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 gelplus faropenem for 4 weeks.

514

N. Hayashi and M. Kawashima

at baseline (P < 0.05). The symptoms scale scores significantly

decreased only after 4 weeks of treatment in group C compared

with those at baseline (P < 0.05). No significant differences in any of

the scores were observed between the three groups (P ‡ 0.05).

DISCUSSION

Although the percentage reduction in inflammatory 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, combina-

tion therapy with adapalene and faropenem decreased the time

required to reduce inflammatory lesions by half. Improvement of

inflammatory 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 prob-

lem. Thus, we propose that oral antibiotics should be used concom-

itantly 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 combi-

nation therapy with adapalene and faropenem was adequate for

� 2011 Japanese Dermatological Association

Combination adapalene ⁄ faropenem for acne

treatment of moderate to severe inflammatory acne. In a random-

ized controlled trial comparing minocycline, roxithromycin and

faropenem that were administrated p.o. for 4 weeks followed by

4 weeks of follow-up observation, inflammatory lesion counts were

reduced by approximately 60% after 4 weeks of treatment with the

oral antibiotics, and their therapeutic effects on inflammatory 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

6–12 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 profiles.

The QOL assessment showed no significant differences in any of

the scores between the three groups. However, the emotions and

functioning scale scores and the total scores significantly 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 significantly decreased only after 4 weeks of treatment

in group C compared with those at baseline. Because the combina-

tion therapy with adapalene and faropenem for 4 weeks produced

better therapeutic effects on inflammatory lesions, the therapy may

have exerted a beneficial influence on the QOL.

The results of this study revealed better and earlier effects of

combination therapy with adapalene and oral antibiotics. They sup-

ported the Japanese Guideline1 that strongly recommends combi-

nation 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 inflammatory lesions. However, a duration of

4 weeks was suggested to be necessary for achieving better out-

comes with the combination therapy.

ACKNOWLEDGMENTS

We are extremely grateful to attending physicians at the medi-

cal institutions listed below for participating in the conduct of

this study. Drs Toshiya Asai, Asai Dermatology Clinic; Hiroyuki

Asanuma, Takashi Onozuka, Yumiko Koike, Asanuma Derma-

tology 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,

� 2011 Japanese Dermatological Association

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, Murah-

ashi 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, honorifics omitted.)

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