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J Dermatolog Treat, 2015; 26(2): 143146

! 2014 Informa UK Ltd. DOI: 10.3109/09546634.2014.921661

ORIGINAL RESEARCH

A randomized controlled trial of combination treatment with

ketoconazole 2% cream and adapalene 0.1% gel in pityriasis versicolor
Tian-Wei Shi1,2*, Jiang-An Zhang2*, Yong-Bo Tang3, Hong-Xing Yu4, Zhan-Guo Li5, and Jian-Bin Yu2
1
Department of Dermatology, Peoples Hospital of Zhengzhou, Zhengzhou, China, 2Department of Dermatology, First Affiliated Hospital of
Zhengzhou University, Zhengzhou, China, 3Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou,
China, 4Department of Science and Education, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China, and 5Department of
Dermatology, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China

Abstract Keywords
Background: Ketoconazole cream and adapalene gel are effective drugs against pityriasis Adapalene, combination, ketoconazole,
versicolor. However, there are no reports on combination treatment with both compounds in pityriasis versicolor, treatment
pityriasis versicolor. Objective: To evaluate the efficacy and safety of combination therapy
with adapalene 0.1% gel and ketoconazole 2% cream against pityriasis versicolor. History
Methods: Participants with pityriasis versicolor were randomly assigned to two groups: the
combination group was treated with adapalene 0.1% gel and ketoconazole 2% cream once Received 6 December 2013
daily, and the monotherapy group received ketoconazole 2% cream twice daily. The treatment Revised 19 March 2014
lasted 2 weeks in both groups. Outcomes were assessed at baseline and 1, 2 and 4 weeks after Accepted 19 March 2014
the initiation of treatment. Results: We noted clinically significant differences in total Published online 3 June 2014
improvement rates between groups Weeks 1 and 2. A statistically significant difference was
obtained Week 4. The treatment was well tolerated by all participants. Conclusions: The
combination of adapalene 0.1% gel and ketoconazole 2% cream is effective and safe in the
treatment of pityriasis versicolor. This therapeutic regimen was rapid, providing a valuable
option for patients with pityriasis versicolor.

Introduction a tretinoin derivative, causes less irritation compared with other

topical retinoid products (9,10) and is efficacious against
Pityriasis versicolor is a chronic superficial fungal infection that is
pityriasis versicolor (11).
caused by Malassezia species and is characterized by hypopig-
Thus, we examined the combination of ketoconazole cream
mented or hyperpigmented macules with delicate scaling,
and adapalene gel in this disease. Considering the strip action of
primarily on the upper trunk and neck (1). This disease is most
adapalene on superficial skin, we postulated that the efficacy of
prevalent in young and middle-aged persons who live in regions
this combination is non-inferior or superior to that of monother-
with high humidity and high temperatures (2). The diagnosis of
apy with ketocanozole cream a hypothesis that we tested in a
pityriasis versicolor is based on clinical signs and symptoms and
clinical trial.
confirmed by direct microscopy (3,4).
Current therapeutic approaches to pityriasis versicolor are
Subjects and methods
focused on synthetic antifungal drugs (5,6), e.g. ketoconazole is
effective against pityriasis versicolor (2). However, due to the Study participants
frequent recurrence of this disease, there has been a widespread
All patients from the outpatient departments of our hospitals were
and reiterative application of azole drugs, and as a result, resistant
Han people who suffered from pityriasis versicolor and were
strains have emerged gradually, leading to increasingly failed
recruited between December 2011 and December 2012. All
treatment against resistant strains (7,8). To improve the efficacy
participants signed informed consent forms before enrollment.
of drugs and prevent the development of resistant strains,
The inclusion criteria were age 18 years; confirmation of
combination treatment might be a viable option. Other non-
symptoms of all hyperpigmented rashes by direct microscopy;
specific antifungal drugs, such as retinoic acid cream, are also
ability to communicate effectively with the study personnel, and
effective against pityriasis versicolor. In particular, adapalene gel,
adequate knowledge of the properties and risks of the study before
screening. The exclusion criteria were hypopigmented lesions; a
known hypersensitivity or allergy to adapalene gel or ketocon-
*These authors contributed equally to this work. azole cream; use of systemic or topical antimycotic agents in the
Correspondence: Jian-Bin Yu, Department of Dermatology, First
most recent month prior to baseline visit; other fungal infectious
Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, diseases, such as malassezia folliculitis, tinea pedis, tinea manus
Zhengzhou 450052, China. Tel: + 86 13938500592. E-mail: and tinea corporis; pregnant women or nursing mothers; signifi-
doctoryu666@163.com cant heart, renal or hepatic disease; and other medical conditions
144 T.-W. Shi et al. J Dermatolog Treat, 2015; 26(2): 143146

that would have prevented completion of the study or produced visit, all patients and investigators determined the tolerability of
significant risks to the patient. the treatment.

Trial design Sample size

This study was a prospective and randomized controlled trial with In a preliminary experiment, the total improvement rates of
an allocation ratio of 1:1. The study was performed per the combination therapy and monotherapy were 95% and 70%,
Declaration of Helsinki, and the study protocol was reviewed and respectively. Forty-five patients in each group were needed, based
approved by the hospitals medical ethics committee and regis- on 0.8 power, to detect a significant difference (p50.05, two-
tered (registry number ChiCTR-TRC-13003356). Before recruit- sided), taking into account a loss to follow-up of 10%. Thus, 50
ment, we generated a randomization list using software, which participants (100 in total) were required in each group, and taking
was available only to certain staff and kept confidential from all into account that 20% of patients would not qualify for
recruiters, assessors and pharmacists. Staff members with access randomization, we planned to recruit 120 patients at the
to this list did not participate in the treatment assessment or enrollment stage.
statistical analysis. All investigators and participants were blinded
to the treatment assignment. After completion of the recruitment, Statistical analysis
data collection, and statistical analyses, the researchers were made
Before the treatment, we compared data on ages, duration and
aware of the randomization sequence.
serious extent of the disease by t-test. The total improvement rates
Participants were randomly assigned to two groups per the
between groups were compared by chi-square (2) test. p50.05
randomization list. Independent pharmacists dispensed ketocono-
was considered significant. If a significant difference between
zole 2% cream or adapalene 0.1% gel according to the numbers
total improvement rates between groups was observed, then 95%
that were designated by the statistician. Patients in Group 1
confidence intervals (95% CIs) would be calculated for the
(combination group) were treated with adapalene 0.1% gel and
difference in total improvement rate of the combination group
ketoconazole 2% cream once daily, and only ketoconazole 2%
minus that of the monotherapy group. We defined the treatment as
cream was applied twice daily in Group 2 (monotherapy group).
non-inferior when the 95% CI was above 15%, superior when
The treatment lasted 2 weeks in both groups. Patients were asked
the 95% CI was 40 and clinically superior when the 95% CI was
to return on the scheduled assessment days (baseline and 1, 2 and
415%. The analysis of total improvement rates was performed on
4 weeks after the initiation of treatment) and report adverse
an intention-to-treat basis.
events.
Results
Efficacy endpoints
The workflow is shown in Figure 1. During the follow-up stage,
The evaluation included laboratory and clinical assessments. The
48 participants in the combination group completed all return
laboratory assessments comprised direct microscopic fungal
visits versus 47 in the monotherapy group. The demographics and
examination at each visit, and examination of scrapings of the
background characteristics, including duration of disease and
scales from several sites by microscopy; patients were scored
average score of the assessment, did not differ between groups
positive or negative. In the clinical assessments, clinical signs and
(Table 1). At the earliest time point (1 week after the beginning of
symptoms with regard to scaling, hyperpigmentation and pruritus
treatment), the total improvement rate was 38% in the combin-
were scored on a 4-point scale (0 absent, 1 mild, 2 mod-
ation group and 6% in the monotherapy group (p 0.000); in the
erate and 3 severe). Improvements in clinical signs and
second week of treatment, these rates were 88% and 56%,
symptoms were classified into five stages: significantly improved
respectively (p 0.000).
(75% improvement), improved (50%, 575% improvement),
During the Weeks 1 and 2 of the treatment, clinically
slightly improved (40%, 550% improvement), unchanged
significant differences in total improvement rates between
(0% improvement) and aggravated.
groups were noted (Week 1: 95% CI [17.02%, 46.98%], Week
Efficacy criteria were based on the laboratory and clinical
2: 95% CI [15.55%, 48.45%]). Similar results were observed in
assessments. Based on negative laboratory results, the percentage
Week 4 the total improvement rate was 92% in the combination
of significantly improved or improved cases was considered the
group and 72% in the monotherapy group (p 0.009; 95% CI
total improvement rate.
[5.46%, 34.54%]) (Table 2). There was good agreement between
the participants and investigators assessments of treatment
Outcome measures
outcomes.
We defined the total improvement rate 4 weeks after treatment
initiation as the primary outcome measure and the total improve- Safety and tolerability
ment rates after 1 and 2 weeks of treatment as secondary outcome
measures. Treatment was terminated when the clinical signs and No serious adverse events were reported. There were eight
symptoms resolved and the fungus was eradicated simultaneously patients with adverse events that were drug-related: five patients
during the therapy, but patients in whom this occurred were asked had erythema, skin dryness, or a burning sensation in the
to make the subsequent visits until the entire assessment was combination group, and three developed mild irritation in the
completed. If serious adverse events occurred or if patients could monotherapy group (p NS). All adverse reactions were mild,
not tolerate the drugs, treatment was discontinued, but all local, and short term, and none interrupted the therapy. The
available data would be recorded. treatment regimens were well tolerated.

Safety endpoints Discussion

All participants were included in the safety analysis. All adverse In this study, we found that the combination of ketoconazole 2%
events and tolerability were recorded using a questionnaire and cream and adapalene 0.1% gel had a more significant effect
participant statements. The adverse events were scored as follows: against pityriasis versicolor than ketoconazole 2% cream alone.
0 absent, 1 mild, 2 moderate and 3 severe. At the last Especially, at earlier time points (1 and 2 weeks after the initiation
DOI: 10.3109/09546634.2014.921661 Ketoconazole and adapalene in pityriasis versicolor 145
Figure 1. About 120 patients were assessed
for eligibility, 20 patients were excluded for
the reasons of not meeting the inclusion
criteria or declining to participate. During
the follow-up stage, 48 participants in
combination group completed all return
visits versus 47 in monotherapy group.

Table 1. Demographic data, duration and average score in both groups at baseline.

Sex (M/F) Age (years) Duration (months) Scores (average) Severe cases/n* (4 scores) (rate)
Combination group 29/21 25.8 6.5 1.7 1.3 2.8 0.9 14/50 (28%)
Monotherapy group 27/23 28.5 7.3 1.5 1.1 2.6 1.0 11/50 (22%)
Statistics 2 0.16 (P1) t 1.95 (P2) t 0.83 (P3) t 1.05 (P4) 2 0.48 (P5)

Comparisons of sex, age, duration and average score between the two groups were not significant difference. P10.687, P2 0.054, P3 0.411,
P4 0.299, P50.488.
*Severe cases were the patients of clinical assessment scores 4; n was the number of the total cases in each group.

Table 2. The efficacy analysis on intention-to-treat basis at weeks 1, 2

and 4.
With regard to mechanism, we presumed that adapalene had
keratolytic activity and adjusting capacity to epithelial cellular
Total improved rates (%)
proliferation and differentiation, which cleared Malassezia yeast
by influencing the fungal environment. Moreover, these could
Week 1 Week 2 Week 4 enhance the penetration of ketoconazole cream into the stratum
Combination 19/50 (38%) 44/50 (88%) 46/50 (92%) corneum, increasing its potency.
group The combination of adapalene 0.1% gel and ketoconazole 2%
Monotherapy 3/50 (6%) 28/50 (56%) 36/50 (72%) cream was generally well tolerated, rendering it a valuable option
group for the treatment of pityriasis versicolor. This regimen was
2 values 21 14.92 (P1*) 22 12.7 (P2*) 24 6.78 (P4*) especially suitable for patients with thick scales and hyperpig-
95% CI** 17.02%, 46.98% 15.55%, 48.45% 5.46%, 34.54%
mented rashes.
*P1, P2, P450.05 (P1 0.000, P2 0.000, P4 0.009). The limitations of this trial were as follows: (1) The
**95% CI for the difference (the total improved rate of combination group sample size was not very large. (2) Patients with hypopigmented
minus that of monotherapy group). lesions were excluded. Because hypopigmentation can persist
for weeks or months after the clearance of fungi, we
excluded patients with hypopigmented rashes. (3) We did not
of treatment), clinical superiority of the combination treatment compare regimens between the like treatment groups
was observed, and statistical superiority was noted after 4 weeks. e.g. ketoconazole cream twice daily versus two separate top-
The improvement was faster and greater in the combination group ical drugs once daily which could have led to some unblinding.
versus the monotherapy group. Thus, we believe that the rapid (4) The lack of long-term follow-up to assess safety and relapse
effect of the combination treatment will prevent drug resistance. was also a limitation, necessitating future studies that address
However, in Week 4, the 95% CI of the difference between groups these issues.
did not exceed 15%, demonstrating that it did not reach the
clinical margin. One of the reasons might be that ketoconazole Acknowledgements
cream gradually became efficacious during the extension treat- The authors greatly appreciate professor Lu Nianzu (Department of
ment, which does not detract from our conclusions. Due to the Dermatology, the First Affiliated Hospital of Sun Yat-Sen University) for
wide confidence intervals, a larger sample size will be needed in his outstanding work on the study and thank the patients who participated
subsequent studies. in this trial.
146 T.-W. Shi et al.
Declaration of interest
The authors have no conflicts of interest to declare.
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