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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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T
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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: [email protected]
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
512
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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