http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–4 ! 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
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
1
Department of Dermatology, People’s 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 versicolor. However, there are no reports on combination treatment with both compounds in pityriasis versicolor. Objective: To evaluate the efficacy and safety of combination therapy with adapalene 0.1% gel and ketoconazole 2% cream against pityriasis versicolor. 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 daily, and the monotherapy group received ketoconazole 2% cream twice daily. The treatment lasted 2 weeks in both groups. Outcomes were assessed at baseline and 1, 2 and 4 weeks after the initiation of treatment. Results: We noted clinically significant differences in total 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.
Adapalene, combination, ketoconazole, pityriasis versicolor, treatment
Introduction Pityriasis versicolor is a chronic superficial fungal infection that is caused by Malassezia species and is characterized by hypopigmented or hyperpigmented macules with delicate scaling, primarily on the upper trunk and neck (1). This disease is most prevalent in young and middle-aged persons who live in regions with high humidity and high temperatures (2). The diagnosis of pityriasis versicolor is based on clinical signs and symptoms and confirmed by direct microscopy (3,4). Current therapeutic approaches to pityriasis versicolor are focused on synthetic antifungal drugs (5,6), e.g. ketoconazole is effective against pityriasis versicolor (2). However, due to the frequent recurrence of this disease, there has been a widespread and reiterative application of azole drugs, and as a result, resistant strains have emerged gradually, leading to increasingly failed treatment against resistant strains (7,8). To improve the efficacy of drugs and prevent the development of resistant strains, combination treatment might be a viable option. Other nonspecific antifungal drugs, such as retinoic acid cream, are also effective against pityriasis versicolor. In particular, adapalene gel,
*These authors contributed equally to this work. Correspondence: Jian-Bin Yu, Department of Dermatology, First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou 450052, China. Tel: + 86 13938500592. E-mail: [email protected]
History Received 6 December 2013 Revised 19 March 2014 Accepted 19 March 2014 Published online 3 June 2014
a tretinoin derivative, causes less irritation compared with other topical retinoid products (9,10) and is efficacious against pityriasis versicolor (11). Thus, we examined the combination of ketoconazole cream and adapalene gel in this disease. Considering the strip action of adapalene on superficial skin, we postulated that the efficacy of this combination is non-inferior or superior to that of monotherapy with ketocanozole cream – a hypothesis that we tested in a clinical trial.
Subjects and methods Study participants All patients from the outpatient departments of our hospitals were Han people who suffered from pityriasis versicolor and were recruited between December 2011 and December 2012. All participants signed informed consent forms before enrollment. The inclusion criteria were age 18 years; confirmation of symptoms of all hyperpigmented rashes by direct microscopy; ability to communicate effectively with the study personnel, and 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 ketoconazole cream; use of systemic or topical antimycotic agents in the most recent month prior to baseline visit; other fungal infectious diseases, such as malassezia folliculitis, tinea pedis, tinea manus and tinea corporis; pregnant women or nursing mothers; significant heart, renal or hepatic disease; and other medical conditions
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
2
T.-W. Shi et al.
J Dermatolog Treat, Early Online: 1–4
that would have prevented completion of the study or produced significant risks to the patient.
visit, all patients and investigators determined the tolerability of the treatment.
Trial design
Sample size
This study was a prospective and randomized controlled trial with an allocation ratio of 1:1. The study was performed per the Declaration of Helsinki, and the study protocol was reviewed and approved by the hospital’s medical ethics committee and registered (registry number ChiCTR-TRC-13003356). Before recruitment, we generated a randomization list using software, which was available only to certain staff and kept confidential from all recruiters, assessors and pharmacists. Staff members with access to this list did not participate in the treatment assessment or statistical analysis. All investigators and participants were blinded to the treatment assignment. After completion of the recruitment, data collection, and statistical analyses, the researchers were made aware of the randomization sequence. Participants were randomly assigned to two groups per the randomization list. Independent pharmacists dispensed ketoconozole 2% cream or adapalene 0.1% gel according to the numbers that were designated by the statistician. Patients in Group 1 (combination group) were treated with adapalene 0.1% gel and ketoconazole 2% cream once daily, and only ketoconazole 2% cream was applied twice daily in Group 2 (monotherapy group). The treatment lasted 2 weeks in both groups. Patients were asked to return on the scheduled assessment days (baseline and 1, 2 and 4 weeks after the initiation of treatment) and report adverse events.
In a preliminary experiment, the total improvement rates of combination therapy and monotherapy were 95% and 70%, respectively. Forty-five patients in each group were needed, based on 0.8 power, to detect a significant difference (p50.05, twosided), taking into account a loss to follow-up of 10%. Thus, 50 participants (100 in total) were required in each group, and taking into account that 20% of patients would not qualify for randomization, we planned to recruit 120 patients at the enrollment stage.
Efficacy endpoints The evaluation included laboratory and clinical assessments. The laboratory assessments comprised direct microscopic fungal examination at each visit, and examination of scrapings of the scales from several sites by microscopy; patients were scored positive or negative. In the clinical assessments, clinical signs and symptoms with regard to scaling, hyperpigmentation and pruritus were scored on a 4-point scale (0 ¼ absent, 1 ¼ mild, 2 ¼ moderate and 3 ¼ severe). Improvements in clinical signs and symptoms were classified into five stages: significantly improved (75% improvement), improved (50%, 575% improvement), slightly improved (40%, 550% improvement), unchanged (0% improvement) and aggravated. Efficacy criteria were based on the laboratory and clinical assessments. Based on negative laboratory results, the percentage of significantly improved or improved cases was considered the total improvement rate. Outcome measures
Statistical analysis Before the treatment, we compared data on ages, duration and serious extent of the disease by t-test. The total improvement rates between groups were compared by chi-square ( 2) test. p50.05 was considered significant. If a significant difference between total improvement rates between groups was observed, then 95% confidence intervals (95% CIs) would be calculated for the difference in total improvement rate of the combination group minus that of the monotherapy group. We defined the treatment as non-inferior when the 95% CI was above 15%, superior when the 95% CI was 40 and clinically superior when the 95% CI was 415%. The analysis of total improvement rates was performed on an intention-to-treat basis.
Results The workflow is shown in Figure 1. During the follow-up stage, 48 participants in the combination group completed all return visits versus 47 in the monotherapy group. The demographics and background characteristics, including duration of disease and average score of the assessment, did not differ between groups (Table 1). At the earliest time point (1 week after the beginning of treatment), the total improvement rate was 38% in the combination group and 6% in the monotherapy group (p ¼ 0.000); in the second week of treatment, these rates were 88% and 56%, respectively (p ¼ 0.000). During the Weeks 1 and 2 of the treatment, clinically significant differences in total improvement rates between groups were noted (Week 1: 95% CI [17.02%, 46.98%], Week 2: 95% CI [15.55%, 48.45%]). Similar results were observed in Week 4 – the total improvement rate was 92% in the combination group and 72% in the monotherapy group (p ¼ 0.009; 95% CI [5.46%, 34.54%]) (Table 2). There was good agreement between the participant’s and investigator’s assessments of treatment outcomes.
We defined the total improvement rate 4 weeks after treatment initiation as the primary outcome measure and the total improvement rates after 1 and 2 weeks of treatment as secondary outcome measures. Treatment was terminated when the clinical signs and symptoms resolved and the fungus was eradicated simultaneously during the therapy, but patients in whom this occurred were asked to make the subsequent visits until the entire assessment was completed. If serious adverse events occurred or if patients could not tolerate the drugs, treatment was discontinued, but all available data would be recorded.
No serious adverse events were reported. There were eight patients with adverse events that were drug-related: five patients had erythema, skin dryness, or a burning sensation in the combination group, and three developed mild irritation in the monotherapy group (p ¼ NS). All adverse reactions were mild, local, and short term, and none interrupted the therapy. The treatment regimens were well tolerated.
Safety endpoints
Discussion
All participants were included in the safety analysis. All adverse events and tolerability were recorded using a questionnaire and participant statements. The adverse events were scored as follows: 0 ¼ absent, 1 ¼ mild, 2 ¼ moderate and 3 ¼ severe. At the last
In this study, we found that the combination of ketoconazole 2% cream and adapalene 0.1% gel had a more significant effect against pityriasis versicolor than ketoconazole 2% cream alone. Especially, at earlier time points (1 and 2 weeks after the initiation
Safety and tolerability
Ketoconazole and adapalene in pityriasis versicolor
DOI: 10.3109/09546634.2014.921661
3
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
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.
Combination group Monotherapy group Statistics
Sex (M/F)
Age (years)
Duration (months)
Scores (average)
Severe cases/n* (4 scores) (rate)
29/21 27/23 2 ¼ 0.16 (P1)
25.8 ± 6.5 28.5 ± 7.3 t ¼ 1.95 (P2)
1.7 ± 1.3 1.5 ± 1.1 t ¼ 0.83 (P3)
2.8 ± 0.9 2.6 ± 1.0 t ¼ 1.05 (P4)
14/50 (28%) 11/50 (22%) 2 ¼ 0.48 (P5)
Comparisons of sex, age, duration and average score between the two groups were not significant difference. P1¼0.687, P2 ¼ 0.054, P3 ¼ 0.411, P4 ¼ 0.299, P5¼0.488. *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. Total improved rates (%)
Combination group Monotherapy group 2 values 95% CI**
Week 1
Week 2
Week 4
19/50 (38%)
44/50 (88%)
46/50 (92%)
3/50 (6%)
28/50 (56%)
36/50 (72%)
21 ¼ 14.92 (P1*) 17.02%, 46.98%
22 ¼ 12.7 (P2*) 15.55%, 48.45%
24 ¼ 6.78 (P4*) 5.46%, 34.54%
*P1, P2, P450.05 (P1 ¼ 0.000, P2 ¼ 0.000, P4 ¼ 0.009). **95% CI for the difference (the total improved rate of combination group minus that of monotherapy group).
of treatment), clinical superiority of the combination treatment was observed, and statistical superiority was noted after 4 weeks. The improvement was faster and greater in the combination group versus the monotherapy group. Thus, we believe that the rapid effect of the combination treatment will prevent drug resistance. However, in Week 4, the 95% CI of the difference between groups did not exceed 15%, demonstrating that it did not reach the clinical margin. One of the reasons might be that ketoconazole cream gradually became efficacious during the extension treatment, which does not detract from our conclusions. Due to the wide confidence intervals, a larger sample size will be needed in subsequent studies.
With regard to mechanism, we presumed that adapalene had keratolytic activity and adjusting capacity to epithelial cellular proliferation and differentiation, which cleared Malassezia yeast by influencing the fungal environment. Moreover, these could enhance the penetration of ketoconazole cream into the stratum corneum, increasing its potency. The combination of adapalene 0.1% gel and ketoconazole 2% cream was generally well tolerated, rendering it a valuable option for the treatment of pityriasis versicolor. This regimen was especially suitable for patients with thick scales and hyperpigmented rashes. The limitations of this trial were as follows: (1) The sample size was not very large. (2) Patients with hypopigmented 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 compare regimens between the like treatment groups – e.g. ketoconazole cream twice daily versus two separate topical drugs once daily – which could have led to some unblinding. (4) The lack of long-term follow-up to assess safety and relapse was also a limitation, necessitating future studies that address these issues.
Acknowledgements The authors greatly appreciate professor Lu Nianzu (Department of Dermatology, the First Affiliated Hospital of Sun Yat-Sen University) for his outstanding work on the study and thank the patients who participated in this trial.
4
T.-W. Shi et al.
Declaration of interest The authors have no conflicts of interest to declare.
References
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
1. Gupta AK, Batra R, Bluhm R, et al. Pityriasis versicolor. Dermatol Clin. 2003;21:413–29. 2. Odom RB, James WD, Berger TG, eds. Diseases resulting from fungi and yeasts. In: Andrews’ Diseases of the Skin. 9th ed. Philadelphia: WB Saunders, 2000. p 358–416. 3. Borelli D, Jacobs PH, Nall L. Tinea versicolor: epidemiologic, clinical and therapeutics aspects. J Am Acad Dermatol. 1991;25: 300–5. 4. Elewski BE. Cutaneous mycoses in children. Br J Dermatol. 1996; 134(Suppl. 46):7–11. 5. Yazdanpanah MJ, Azizi H, Suizi B. Comparison between fluconazole and ketoconazole effectivity in the treatment of pityriasis versicolor. Mycoses. 2007;50:311–13.
J Dermatolog Treat, Early Online: 1–4
6. Rigopoulos D, Gregoriou S, Kontochristopoulos G, et al. Flutrimazole shampoo 1% versus ketoconazole shampoo 2% in the treatment of pityriasis versicolor. A randomised double-blind comparative trial. Mycoses. 2007;50:193–5. 7. Wroblewska MM, Swoboda-Kopec E, Rokosz A, et al. Epidermiology of clinical isolates of Candida albicans and their susceptibility to triazoles. Int J Antimicrob Agents. 2002;20:472–5. 8. Snelders E, vander Lee HA, Kuijpers J, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5:219. 9. Verschoore M, Poncet M, Czernielewski J, et al. Adapalene 0.1% gel has low skin-irritation potential. J Am Acad Dermatol. 1997;36: S104–9. 10. Brand B, Gilbert R, Baker MD, et al. Cumulative irritancy comparison of adapalene gel 0.1% versus other retinoid products when applied in combination with topical antimicrobial agents. J Am Acad Dermatol. 2003;49(Suppl. 3):S227–32. 11. Shi TW, Ren XK, Yu HX, et al. Roles of adapalene in the treatment of pityriasis versicolor. Dermatology. 2012;224:184–8.
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
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
1
Department of Dermatology, People’s 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 versicolor. However, there are no reports on combination treatment with both compounds in pityriasis versicolor. Objective: To evaluate the efficacy and safety of combination therapy with adapalene 0.1% gel and ketoconazole 2% cream against pityriasis versicolor. 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 daily, and the monotherapy group received ketoconazole 2% cream twice daily. The treatment lasted 2 weeks in both groups. Outcomes were assessed at baseline and 1, 2 and 4 weeks after the initiation of treatment. Results: We noted clinically significant differences in total 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.
Adapalene, combination, ketoconazole, pityriasis versicolor, treatment
Introduction Pityriasis versicolor is a chronic superficial fungal infection that is caused by Malassezia species and is characterized by hypopigmented or hyperpigmented macules with delicate scaling, primarily on the upper trunk and neck (1). This disease is most prevalent in young and middle-aged persons who live in regions with high humidity and high temperatures (2). The diagnosis of pityriasis versicolor is based on clinical signs and symptoms and confirmed by direct microscopy (3,4). Current therapeutic approaches to pityriasis versicolor are focused on synthetic antifungal drugs (5,6), e.g. ketoconazole is effective against pityriasis versicolor (2). However, due to the frequent recurrence of this disease, there has been a widespread and reiterative application of azole drugs, and as a result, resistant strains have emerged gradually, leading to increasingly failed treatment against resistant strains (7,8). To improve the efficacy of drugs and prevent the development of resistant strains, combination treatment might be a viable option. Other nonspecific antifungal drugs, such as retinoic acid cream, are also effective against pityriasis versicolor. In particular, adapalene gel,
*These authors contributed equally to this work. Correspondence: Jian-Bin Yu, Department of Dermatology, First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou 450052, China. Tel: + 86 13938500592. E-mail: [email protected]
History Received 6 December 2013 Revised 19 March 2014 Accepted 19 March 2014 Published online 3 June 2014
a tretinoin derivative, causes less irritation compared with other topical retinoid products (9,10) and is efficacious against pityriasis versicolor (11). Thus, we examined the combination of ketoconazole cream and adapalene gel in this disease. Considering the strip action of adapalene on superficial skin, we postulated that the efficacy of this combination is non-inferior or superior to that of monotherapy with ketocanozole cream – a hypothesis that we tested in a clinical trial.
Subjects and methods Study participants All patients from the outpatient departments of our hospitals were Han people who suffered from pityriasis versicolor and were recruited between December 2011 and December 2012. All participants signed informed consent forms before enrollment. The inclusion criteria were age 18 years; confirmation of symptoms of all hyperpigmented rashes by direct microscopy; ability to communicate effectively with the study personnel, and 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 ketoconazole cream; use of systemic or topical antimycotic agents in the most recent month prior to baseline visit; other fungal infectious diseases, such as malassezia folliculitis, tinea pedis, tinea manus and tinea corporis; pregnant women or nursing mothers; significant heart, renal or hepatic disease; and other medical conditions
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
2
T.-W. Shi et al.
J Dermatolog Treat, Early Online: 1–4
that would have prevented completion of the study or produced significant risks to the patient.
visit, all patients and investigators determined the tolerability of the treatment.
Trial design
Sample size
This study was a prospective and randomized controlled trial with an allocation ratio of 1:1. The study was performed per the Declaration of Helsinki, and the study protocol was reviewed and approved by the hospital’s medical ethics committee and registered (registry number ChiCTR-TRC-13003356). Before recruitment, we generated a randomization list using software, which was available only to certain staff and kept confidential from all recruiters, assessors and pharmacists. Staff members with access to this list did not participate in the treatment assessment or statistical analysis. All investigators and participants were blinded to the treatment assignment. After completion of the recruitment, data collection, and statistical analyses, the researchers were made aware of the randomization sequence. Participants were randomly assigned to two groups per the randomization list. Independent pharmacists dispensed ketoconozole 2% cream or adapalene 0.1% gel according to the numbers that were designated by the statistician. Patients in Group 1 (combination group) were treated with adapalene 0.1% gel and ketoconazole 2% cream once daily, and only ketoconazole 2% cream was applied twice daily in Group 2 (monotherapy group). The treatment lasted 2 weeks in both groups. Patients were asked to return on the scheduled assessment days (baseline and 1, 2 and 4 weeks after the initiation of treatment) and report adverse events.
In a preliminary experiment, the total improvement rates of combination therapy and monotherapy were 95% and 70%, respectively. Forty-five patients in each group were needed, based on 0.8 power, to detect a significant difference (p50.05, twosided), taking into account a loss to follow-up of 10%. Thus, 50 participants (100 in total) were required in each group, and taking into account that 20% of patients would not qualify for randomization, we planned to recruit 120 patients at the enrollment stage.
Efficacy endpoints The evaluation included laboratory and clinical assessments. The laboratory assessments comprised direct microscopic fungal examination at each visit, and examination of scrapings of the scales from several sites by microscopy; patients were scored positive or negative. In the clinical assessments, clinical signs and symptoms with regard to scaling, hyperpigmentation and pruritus were scored on a 4-point scale (0 ¼ absent, 1 ¼ mild, 2 ¼ moderate and 3 ¼ severe). Improvements in clinical signs and symptoms were classified into five stages: significantly improved (75% improvement), improved (50%, 575% improvement), slightly improved (40%, 550% improvement), unchanged (0% improvement) and aggravated. Efficacy criteria were based on the laboratory and clinical assessments. Based on negative laboratory results, the percentage of significantly improved or improved cases was considered the total improvement rate. Outcome measures
Statistical analysis Before the treatment, we compared data on ages, duration and serious extent of the disease by t-test. The total improvement rates between groups were compared by chi-square ( 2) test. p50.05 was considered significant. If a significant difference between total improvement rates between groups was observed, then 95% confidence intervals (95% CIs) would be calculated for the difference in total improvement rate of the combination group minus that of the monotherapy group. We defined the treatment as non-inferior when the 95% CI was above 15%, superior when the 95% CI was 40 and clinically superior when the 95% CI was 415%. The analysis of total improvement rates was performed on an intention-to-treat basis.
Results The workflow is shown in Figure 1. During the follow-up stage, 48 participants in the combination group completed all return visits versus 47 in the monotherapy group. The demographics and background characteristics, including duration of disease and average score of the assessment, did not differ between groups (Table 1). At the earliest time point (1 week after the beginning of treatment), the total improvement rate was 38% in the combination group and 6% in the monotherapy group (p ¼ 0.000); in the second week of treatment, these rates were 88% and 56%, respectively (p ¼ 0.000). During the Weeks 1 and 2 of the treatment, clinically significant differences in total improvement rates between groups were noted (Week 1: 95% CI [17.02%, 46.98%], Week 2: 95% CI [15.55%, 48.45%]). Similar results were observed in Week 4 – the total improvement rate was 92% in the combination group and 72% in the monotherapy group (p ¼ 0.009; 95% CI [5.46%, 34.54%]) (Table 2). There was good agreement between the participant’s and investigator’s assessments of treatment outcomes.
We defined the total improvement rate 4 weeks after treatment initiation as the primary outcome measure and the total improvement rates after 1 and 2 weeks of treatment as secondary outcome measures. Treatment was terminated when the clinical signs and symptoms resolved and the fungus was eradicated simultaneously during the therapy, but patients in whom this occurred were asked to make the subsequent visits until the entire assessment was completed. If serious adverse events occurred or if patients could not tolerate the drugs, treatment was discontinued, but all available data would be recorded.
No serious adverse events were reported. There were eight patients with adverse events that were drug-related: five patients had erythema, skin dryness, or a burning sensation in the combination group, and three developed mild irritation in the monotherapy group (p ¼ NS). All adverse reactions were mild, local, and short term, and none interrupted the therapy. The treatment regimens were well tolerated.
Safety endpoints
Discussion
All participants were included in the safety analysis. All adverse events and tolerability were recorded using a questionnaire and participant statements. The adverse events were scored as follows: 0 ¼ absent, 1 ¼ mild, 2 ¼ moderate and 3 ¼ severe. At the last
In this study, we found that the combination of ketoconazole 2% cream and adapalene 0.1% gel had a more significant effect against pityriasis versicolor than ketoconazole 2% cream alone. Especially, at earlier time points (1 and 2 weeks after the initiation
Safety and tolerability
Ketoconazole and adapalene in pityriasis versicolor
DOI: 10.3109/09546634.2014.921661
3
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
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.
Combination group Monotherapy group Statistics
Sex (M/F)
Age (years)
Duration (months)
Scores (average)
Severe cases/n* (4 scores) (rate)
29/21 27/23 2 ¼ 0.16 (P1)
25.8 ± 6.5 28.5 ± 7.3 t ¼ 1.95 (P2)
1.7 ± 1.3 1.5 ± 1.1 t ¼ 0.83 (P3)
2.8 ± 0.9 2.6 ± 1.0 t ¼ 1.05 (P4)
14/50 (28%) 11/50 (22%) 2 ¼ 0.48 (P5)
Comparisons of sex, age, duration and average score between the two groups were not significant difference. P1¼0.687, P2 ¼ 0.054, P3 ¼ 0.411, P4 ¼ 0.299, P5¼0.488. *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. Total improved rates (%)
Combination group Monotherapy group 2 values 95% CI**
Week 1
Week 2
Week 4
19/50 (38%)
44/50 (88%)
46/50 (92%)
3/50 (6%)
28/50 (56%)
36/50 (72%)
21 ¼ 14.92 (P1*) 17.02%, 46.98%
22 ¼ 12.7 (P2*) 15.55%, 48.45%
24 ¼ 6.78 (P4*) 5.46%, 34.54%
*P1, P2, P450.05 (P1 ¼ 0.000, P2 ¼ 0.000, P4 ¼ 0.009). **95% CI for the difference (the total improved rate of combination group minus that of monotherapy group).
of treatment), clinical superiority of the combination treatment was observed, and statistical superiority was noted after 4 weeks. The improvement was faster and greater in the combination group versus the monotherapy group. Thus, we believe that the rapid effect of the combination treatment will prevent drug resistance. However, in Week 4, the 95% CI of the difference between groups did not exceed 15%, demonstrating that it did not reach the clinical margin. One of the reasons might be that ketoconazole cream gradually became efficacious during the extension treatment, which does not detract from our conclusions. Due to the wide confidence intervals, a larger sample size will be needed in subsequent studies.
With regard to mechanism, we presumed that adapalene had keratolytic activity and adjusting capacity to epithelial cellular proliferation and differentiation, which cleared Malassezia yeast by influencing the fungal environment. Moreover, these could enhance the penetration of ketoconazole cream into the stratum corneum, increasing its potency. The combination of adapalene 0.1% gel and ketoconazole 2% cream was generally well tolerated, rendering it a valuable option for the treatment of pityriasis versicolor. This regimen was especially suitable for patients with thick scales and hyperpigmented rashes. The limitations of this trial were as follows: (1) The sample size was not very large. (2) Patients with hypopigmented 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 compare regimens between the like treatment groups – e.g. ketoconazole cream twice daily versus two separate topical drugs once daily – which could have led to some unblinding. (4) The lack of long-term follow-up to assess safety and relapse was also a limitation, necessitating future studies that address these issues.
Acknowledgements The authors greatly appreciate professor Lu Nianzu (Department of Dermatology, the First Affiliated Hospital of Sun Yat-Sen University) for his outstanding work on the study and thank the patients who participated in this trial.
4
T.-W. Shi et al.
Declaration of interest The authors have no conflicts of interest to declare.
References
J Dermatolog Treat Downloaded from informahealthcare.com by University of Washington on 01/15/15 For personal use only.
1. Gupta AK, Batra R, Bluhm R, et al. Pityriasis versicolor. Dermatol Clin. 2003;21:413–29. 2. Odom RB, James WD, Berger TG, eds. Diseases resulting from fungi and yeasts. In: Andrews’ Diseases of the Skin. 9th ed. Philadelphia: WB Saunders, 2000. p 358–416. 3. Borelli D, Jacobs PH, Nall L. Tinea versicolor: epidemiologic, clinical and therapeutics aspects. J Am Acad Dermatol. 1991;25: 300–5. 4. Elewski BE. Cutaneous mycoses in children. Br J Dermatol. 1996; 134(Suppl. 46):7–11. 5. Yazdanpanah MJ, Azizi H, Suizi B. Comparison between fluconazole and ketoconazole effectivity in the treatment of pityriasis versicolor. Mycoses. 2007;50:311–13.
J Dermatolog Treat, Early Online: 1–4
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