Ciclopirox is a broad-spectrum antifungal, antibacterial, and anti-inflammatory agent. This open-label study investigated the safety and efficacy of ciclopirox topical suspension 0.77% in the treatment of diaper dermatitis due to Candida albicans (C. albicans). Forty-four male and female subjects aged 6 to 29 months were included in the study. Study medication was applied topically to the affected diaper area twice daily for 1 week. Subjects were clinically evaluated at baseline and days 3, 7, and 14 (7 days post-treatment). Safety and efficacy variables included adverse events, mycological culture studies, KOH tests, Severity Scores, and Global Evaluation of Clinical Response. All adverse events were mild to moderate and considered not related to the study medication. Treatment provided statistically significant improvement (P < .05) for both the rate of mycological cure and reduction of Severity Score at each time point compared with baseline. Ciclopirox was safe and effective in the treatment of diaper dermatitis due to C. albicans.
Diaper dermatitis is the most common dermatologic disorder of infancy and is characterized by acute inflammation of the skin in the diaper area. The reported prevalence of diaper dermatitis ranges from 4% to 15% from birth to 2 years; (1) however, the true prevalence may be much greater since many cases do not reach physicians. Studies have shown that the incidence of diaper dermatitis is highest in infants between the ages of 6 months and 1 year. (2) It is diagnosed during more than 1 million outpatient office visits per year in the United States, (3) and estimates are that fewer than 10% of cases are specifically referred for treatment. (4)
Diaper dermatitis occurs when the skin is exposed to overhydration, frictional damage, and increased pH from the urine/feces mixture, with resulting enhanced activity of fecal enzymes. (2) This combination weakens the barrier function of the stratum corneum and allows increased microbial growth. (5) Alterations of the skin-barrier function also change the normal flora and can promote the growth of Candida albicans (C. albicans). (5)
Candidal dermatitis presents as bright red erythema that involve the folds with satellite pustules. (6) Other microbial infections are less common; however, bacterial super-infections do occur and are characterized by superficial erosions, yellow serum crust, and occasionally bullae. (6) The management and prevention of diaper dermatitis include keeping the area clean and dry by minimizing contact with urine and feces, limiting the irritation and maceration of diaper covering, and maintaining an acidic pH on the skin.
Ciclopirox topical suspension (TS) 0.77% (Loprox[R]) is a broad-spectrum antifungal agent that inhibits the growth of pathogenic dermatophytes and yeasts. (7) It is indicated for topical treatment of a broad range of dermal infections, including candidiasis due to C. albicans; tinea versicolor due to Malassezia furfur; and tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis. (7) Due to the lack of antifungal preparations formulated for use in the diaper area, this study was designed to evaluate the safety and efficacy of ciclopirox TS 0.77% in treating diaper dermatitis due to cutaneous candidiasis.
This open-label study was conducted in accordance with Good Clinical Practice and applicable International Conference on Harmonisation guidelines. The protocol and informed consent were approved by the Western International Review Board, Olympia, Washington. The clinical phase of the study was conducted at 5 sites throughout the United States.
Male and female subjects aged 6 to 23 months, defined as a baseline minimum age of 183 days from the date of birth up to the maximum age whereby the subject had not reached his or her second birthday on the date of the baseline visit, were eligible to participate in the study. Subjects were required to have diaper dermatitis due to cutaneous candidiasis confirmed by a positive baseline KOH test for hyphae, pseudohyphae, or budding yeast. Subjects' parents or guardians were required to commit to all follow-up visits for the study duration, consent to having the subject's affected skin area swabbed for mycological evaluation, and to use the study drug as instructed.
Subjects were excluded from study participation if they met any of the following criteria: known sensitivity to ciclopirox; serious systemic disease or known immunosuppression; receiving medication that may affect study results; and use of other topical antifungals or topical corticosteroids in the diaper area within 1 week of enrollment.
This multicenter, open-label study was conducted to investigate the safety and efficacy of topical application of ciclopirox 0.77% twice daily for 7 days in subjects meeting the inclusion and exclusion criteria.
Screening evaluations performed at baseline (day 0) included obtaining written informed consent as well as a complete medical history. Safety and efficacy assessments were performed at selected times throughout the study as shown in Table 1.
Each subject received a 60-mL bottle of ciclopirox 0.77%. The first dose of study medication was administered during the initial visit to ensure that a sufficient quantity was applied with adequate coverage. Parents/guardians were instructed to apply the study medication to the entire affected area twice daily after bathing the diaper area of the subject with a gentle cleanser, rinsing the subject thoroughly, and patting dry with a soft towel. Applications were made at the time of the first diaper change of the morning and before bedtime for the entire course of study treatment. Parents/guardians were instructed to apply petroleum jelly to the diaper area following diaper changes throughout the day. No other topical products were to be applied to the affected skin. Treatment compliance was verified by weighing the study medication prior to dispensing on day 0 and again on days 3 and 7. Parents/guardians were asked to state verbally the number of times medication was applied daily.
Safety and Efficacy Assessments
Adverse events (AEs) were defined as any untoward medical occurrence in a subject whether or not it was caused by the study medication. AEs were rated regarding severity (mild, moderate, or severe) and relationship to study drug (not related, possibly related, or definitely related). Serious AEs were reported to the Institutional Review Board and to the study sponsor or the study monitor.
Physical and dermatological examinations consisted of height and weight measurements, evaluation of diaper dermatitis relative to inclusion criteria, and examination for gross abnormalities and dermatological conditions other than diaper dermatitis. All safety and mycology assessments were performed using generally recognized and standard methodologies. KOH tests were performed by microscopic evaluation of infected skin specimens. Mycological culture swabs taken from papulopustules, erosions, or ulcerations of lesions were analyzed by the mycology laboratory for the presence or absence of C. albicans. Possible results were as follows: negative--no growth; negative--bacterial overgrowth; positive--C. albicans; and positive--Candida species not albicans.
Efficacy parameters included Severity Scores and Global Evaluation of Clinical Response, both on 5-point scales. Severity Scores were as follows: 0 = clear, no signs of active disease (post-inflammatory discoloration of the skin may be present); 1 = mild erythema with minimal maceration and/or chafing; 2 = moderate erythema with or without satellite papules with maceration and chafing; 3 = severe erythema with papulopustules and maceration; and 4 = extreme erythema with erosions or ulceration. The following scale was used for Global Evaluation of Clinical Response: 0 = cleared, complete clearance of signs and symptoms of disease (post-inflammatory discoloration of the skin may be present); 1 = some residual signs and symptoms present but no further treatment needed; 2 = clearing, but further treatment is needed; 3 = no change, no detectable improvement from baseline evaluation; 4 = exacerbation, worsening of signs and symptoms compared with baseline evaluation. If a subject discontinued early for any reason, the last observation was carried forward and used in the analysis.
Treatment success was defined as combined mycological cure and clinical success at the last observed treatment visit (up to day 7). Mycological cure was defined as a negative KOH test and negative mycological culture results; clinical success was defined as a Severity Score of 0.
Statistical and Analytical Methods
Demographic, Severity Score, Global Evaluation of Clinical Response, and treatment success data were summarized by descriptive statistics. Paired t-tests were used to determine if treatment significantly reduced the severity of diaper dermatitis after days 3, 7, and 14 compared with baseline. Chi-square tests were performed on mycological cure and clinical success data. The frequency of subjects experiencing serious and non-serious AEs were tabulated according to term, severity, and relation to study medication.
A total of 44 subjects were enrolled in the study. All subjects were clinically diagnosed with diaper dermatitis due to C. albicans at the baseline visit. Individual subject demographics are outlined in Table 2. Two subjects failed to meet the inclusion criterion for age. At study entry, 1 subject was 180 days old and 1 subject was 29 months old. Data from these subjects were included in the intent-to-treat analysis. Three subjects discontinued treatment before the end of the study period. Of those, parents/guardians refused continued participation or withdrew consent for 2 of the subjects, and 1 subject was lost to follow-up. Subjects who discontinued prematurely were not replaced.
Study medication was applied to the affected diaper area once in the morning with the first diaper change and once in the evening before bedtime daily for 7 days. Each parent provided a verbal account of how many applications of study medication were made during the course of the study. Across all subjects during the treatment period (days 0 through 7), the total quantity of study medication used was 15.16[+ or -]1.80 g, and the mean number of study medication applications was 14.97[+ or -]0.14.
As shown in Table 3, there were 43 AEs of mild to moderate severity reported during the study. There were no deaths or serious AEs reported. None of the AEs required subjects to discontinue study medication. Physical examinations revealed no findings beyond those of the AEs. Clinical laboratory findings reflected no adverse safety effects.
Of the 44 subjects enrolled in the study, 25 experienced 1 or more AE. For subjects having more than 1 AE (where the AEs were of different severities), only the highest-severity AE was counted. The most frequently reported AEs, occurring in 5% or more of subjects, were pruritus, rash, rhinitis, sinusitis, diarrhea, gastroenteritis, conjunctivitis, and accidental injury. None of the AEs were considered related to the study medication.
Two subjects reported a worsening of diaper rash as an AE; however, it was not considered related to the study medication. In most cases, a worsening of diaper rash was not reported as an AE because the severity assessments captured changes in diaper rash conditions.
Treatment success was defined as both mycological cure (ie, negative mycological culture and negative KOH test) and clinical success (ie, Severity Score = 0). For all study sites combined, the chi-square test results revealed a significant rate of treatment success (P = .0407).
Mycological culture findings compared the frequency of positive and negative mycological cultures between day 0 and day 7 using chi-square tests. Results indicated that treatment significantly reduced the frequency of positive cultures (P < .01) and provided significant rates of mycological cure (P < .01) at the end of 7 days. In addition, KOH results were compared between days 0 and 7 using chi-square tests. Treatment significantly reduced the number of positive KOH results at day 7 compared with baseline (P < .01). However, because many of the cell frequencies were less than 5, these results should be interpreted with caution.
Clinical success data were generated by comparing Severity Score at baseline and days 3, 7, and 14. As shown in Table 4, Severity Scores were reduced at each observation point compared with baseline. Results from the paired t-test comparison of Severity Score (days 0-3, days 0-7, and days 0-14) indicated that treatment significantly reduced Severity Score at each observation compared with baseline (P < .05).
Global Evaluation of Clinical Response scores obtained at days 3, 7, and 14 showed improvement across all visits. There was a clear migration from higher scores to lower scores at each successive visit (Figure 1). At day 3, 5 of 43 subjects showed complete clearance or showed some residual signs and symptoms of disease not requiring any further treatment. However, by day 14, 20 of 41 subjects showed complete clearance (score = 0) and 7 subjects showed residual signs and symptoms not requiring any further treatment (score = 1).
In summary, none of the AEs reported in this study were considered related to the study medication, and no subjects discontinued due to AEs. Treatment provided significant rates of mycological cure at the end of 7 days and also significantly reduced Severity Score at each time point compared with baseline. Global Evaluation of Clinical Response score decreased across study visits.
Because of its broad-spectrum activity, ciclopirox TS 0.77% can be used to control many pathogens, including C. albicans. (7-10) Ciclopirox TS 0.77% is currently indicated for topical treatment of a broad range of dermal infections. In addition to its proven candicidal, fungicidal, and antibacterial activity that includes gram-positive and gram-negative coverage, (10,11) there is also evidence that ciclopirox may exhibit better anti-inflammatory activity than other antifungals and hydrocortisone. (12)
While further studies should be performed within the pediatric population, the antimicrobial and anti-inflammatory properties of ciclopirox may suggest widening the scope of investigation to include the treatment of diaper dermatitis characterized by mixed fungal/bacterial infections, without the addition of a steroid to control inflammation. Also, because no blinding was performed in this study, future randomized, placebo-controlled studies would further elucidate data on the study drug and its safety and efficacy in subjects with diaper dermatitis.
The results of this study indicate that ciclopirox TS 0.77% is safe in the treatment of diaper dermatitis due to C. albicans. Study results also indicate that ciclopirox TS 0.77% is effective in the treatment of diaper dermatitis due to C. albicans as measured by mycological cure, Severity Score, and Global Evaluation of Clinical Response.
Disclosure: Dr. Plott is a full-time employee of Medicis Pharmaceutical Corporation.
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Elizabeth Gallup MD JD MBA, (a) The Ciclopirox TS Investigators, (b) Todd Plott MD (c)
a. Medical Strategies Inc., Mission, KS
b. Anthony Diehl MD, Radiant Research, Eugene, OR; Frank Dunlap MD, Radiant Research, Tucson, AZ; Beth Nauert MD, Radiant Research, Austin TX; H Lee Smyre MD, Radiant Research, Greer, SC
c. Medicis Pharmaceutical Corporation, Scottsdale, AZ
ADDRESS FOR CORRESPONDENCE
Elizabeth Gallup MD JD MBA
Medical Strategies Inc.
5799 Broadmoor, Suite 104
Mission, KS 66202
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