Randomised controlled trial of topical butenafine in tinea cruris and tinea corporis

Introduction

Butenafine hydrochloride (n-4-ter-butyl-benzyl-N-methyl-1-naphthaline methylamine (hydrochloride) is a new benzylamine derivative with a chemical structure and mode of action similar to allylamine antifungals.[1] It inhibits squalene epoxidase, an enzyme which converts squalene to lanosterol and leads to accumulatior of squalene and is primarily fungicidal agains dermatophytes.[2]

The azole antifungals have beer extensively used to treat dermatophytosis since the 1970s.[3] The most commonly used topical agent are clotrimazole and miconazole. The azoles ac as fungistatic agents by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-@-demethylase, which is important for the biosynthesis of ergosterol, a component of fungal cell membrane.[2]

We evaluated the safety and efficacy of butenafine cream 1 % in comparison with topical clotrimazole cream 1 % in the treatment of tinea cruris and corporis in a randomized controlled trial.

Patients and Methods

Patients were recruited from the skin OPD at the All India Institute of Medical Sciences (AIIMS), New Delhi between March and November 2000. The study was approved by the Institute Ethics Committee and the requisite permission of the Drugs Controller General of India (DCGI) was obtained. A written informed consent was obtained from the patients prior to study enrollment.

Patient selection

Patients above the age of 18 with clinical evidence of tinea cruris and/ortinea corporis were clinically evaluated and a potassium hydroxide (KOH) preparation of scrapings from a selected lesion was examined microscopically. The symptoms and signs of erythema, scaling and pruritus were scored on a scale of 1 (nil) to 3 (severe). Patients were eligible for the study if they had a combined score of at least 5. A fungal culture was also performed in all patients but a positive culture was not a pre-requisite for inclusion in the study.

Women who were pregnant or lactating were excluded. Patients with a known history or clinical evidence of severe cardiac, pulmonary, gastrointestinal, renal, hepatic or neurological disease and uncontrolled diabetes mellitus were also excluded from the study. Other reasons for exclusion were a known hypersensitivity to allylamine/benzylamine agents, treatment with systemic antifungal agents in the previous one month, itraconazole in the previous 6 months, systemic antibiotics in the previous 2 weeks, corticosteroids or immunosuppressants in the past 6 weeks, or any investigational drug in the previous 3 months. Patients with contact dermatitis, atopic dermatitis, psoriasis or any other disease that would interfere with the evaluation of the study results were also excluded.

Drug administration

After recruitment, patients were randomly assigned to receive butenafine or clotrimazole cream in a double-blind fashion in blocks of 10 patients. Patients assigned to treatment with butenafine received the active agents in the morning and a placebo (vehicle) in the evening for a period of 2 weeks. After 2 weeks they received placebo cream both in the morning and in the evening for a further 2 weeks. Patients in the clotrimazole received the active twice daily (morning and evening) for 4 weeks.

Patients were given a week′s supply of medication at each visit. The medication consisted of 2 identical tubes of 5 gm labeled "Morning" and "Evening". Patients were instructed to apply the cream to the skin lesion at the appropriate times.

Baseline evaluation and follow up

At the initial visit, eligible patients underwent a complete physical examination and local examination of the selected lesion, measurement of vital signs, and standard laboratory tests. The lesion identified was evaluated for the following signs and symptoms: erythema, scaling, pustules, vesiculation, maceration, papules, and pruritus. Signs and symptoms were scored on a scale of 0 to 3 as follows: 0=none, 1=mild, 2=moderate, 3=severe. The individual scores were added and total score was reported.

Laboratory tests included complete blood count; liver function tests including serum bilirubin, and serum transaminases (SCOT and SGPT), blood urea and serum creatinine; and urine routine and microscopy. A KOH (10%) preparation of the scraping was examined to confirm the presence of hyphae and a fungal culture was undertaken to identify the agent.

The patients were called for follow up after 1, 2 and 4 weeks of treatment and also 4 weeks cessation of treatment. Thus the patient had to make a total of six visits. At each visit, clinical examination of the target lesions, a KOH test and fungal culture were performed. Laboratory investigations were repeated at the end of week 2 and as and when necessary. Adverse events were recorded at each visit.

Efficacy parameters

The efficacy of the two preparations were evaluated and compared on the basis of following parameters:

1) KOH test: A negative KOH preparation at the end of the study period was considered as mycologic cure.

2) Change in the signs and symptoms score.

Relapses were defined as the recording of a positive KOH preparation within 4 weeks after cessation of treatment in a patient in whom the KOH preparation was negative on a earlier occasion.

Statistical analysis

The last observation carried forward (LOCF) method was used to analyse the data. Patients who had completed at least 2 weeks of therapy were included in the analysis. Students paired t-test was used to compare parameters such as age, laboratory values, blood pressure and pulse rate between the groups. Non-parametric Wilcoxon match-paired signed-ranks test was used to compare the sign and symptom scores within the groups. The difference in the change in the total sign and symptom scores between the 2 groups were compared by using a unpaired t-test. Chi square test with yate′s correction was used to evaluate the difference in the mycological cure rate between the two groups.

Results

Results for both groups are reported at 4 weeks after cessation of treatment i.e., results for the butenafine group are reported till week 6 and for the clotrimazole group till week 8 after initiation of the treatment.

Seventy-five patients were enrolled into the study, 37 in the butenafine group and 38 in the clotrimazole group. Fourteen patients in the butenafine group and nine in the clotrimazole group were lost to follow-up. One patient in the butenafine group could not continue the study as both his legs were fractured in a car accident. One patients in the clotrimazole group had to be withdrawn, since she experienced exudation and itching in the affected area after 2 days of treatment. In the butenafine group, 18 patients were followed up till 4 weeks after cessation of treatment, 2 patients till 2 weeks after cessation of treatment and 2 patients till the end of the treatment period. In the clotrimazole treatment group, 24 patients were followed up till 4 weeks after cessation of treatment, 1 patient till 2 weeks after cessation of treatment and 3 patients till 2 weeks of treatment [Figure - 1].

Thus 22 patients in the butenafine group and 28 in the clotrimazole group were included for analysis. The baseline characteristics of the patients are given in [Table - 1].

Efficacy

KOH preparation

In the butenafine group, 20 (90.9%) out of 22 patients showed negative KOH preparation at the end of 2 weeks of treatment. One patient demonstrated a positive KOH preparation 2 weeks after cessation of treatment and this patient continued to be positive till the end of follow up at 6 weeks post treatment. In addition, 85 mycological relapse was seen in 1 patient at 4 weeks post treatment. This group had a mycological cure rate of 90.9% at 4 weeks post treatment follow-up.

In the clotrimazole treated group, 27 (96.4%) out of 28 patients showed negative KOH preparations at the end of 2 weeks of treatment and all the 28 patients were mycologically cured after 4 weeks of treatment. One patient demonstrated a positive KOH preparation 2 weeks after cessation of treatment and two at 4 weeks post treatment. Clotrimazole treated patients had a mycological cure of 92.85% at 4 weeks post treatment follow-up.

There was no statistically significant difference between the 2 groups at the end of treatment, 2 weeks and 4 weeks post treatment (p=0.38, 1.0 respectively).

Fungal culture

In the butenafine group, dermatophytes were grown in 6 (27.27%) out of 22 patients; T rubrum was cultured in 5 patients and E.floccosum in 1 patient. At 2, 4 and 6 weeks all the cultures were negative. Culture was positive in 1 patient at week 8.

In the clotrimazole group, dermatophytes were grown in 8 (28.57%) out of 28 patients; T rubrum was cultured in 7 patients and E.floccosum in 1 patient. At week 2 and 4, cultures were positive in 2 patients. At week 6 all cultures were negative. Culture was positive in 1 patient at week 8.

Sign and symptom score

The sign and symptom score declined significantly in both the groups [Figure - 2]. In the butenafine group, the score declined from a mean of 7.36± at baseline to 1.5± 1.43 at week 2, 1.04± 1.55 at week 4, 1.45± 2.3 at week 6 and 1.5± 2.3 at week 8 [Figure - 1]. The reduction in the sign and symptom score from baseline at 4 weeks post-treatment follow up in the butenafine treated group was 81.5%.

In the clotrimazole group the score reduced from a mean of 7.46+2.4 at baseline to 1.46± 1.42 at week 2, 0.75± 1.04 at week 4, 1.03 ± 1.59 at week 6 and 1.14± 1.91 at week 8. There was 85.93% of reduction in the sign and symptoms score at 4 weeks post-treatment follow up in clotrimazole group.

There was no statistically significant difference between the 2 groups in the percent reduction in the sign and the symptom scores after 4 weeks of cessation of treatment (p=0.63).

Adverse events

Adverse events experienced in the butenafine group were burning (two patients), pruritus (two patients), striae (one patient) and erythema with atropy (one patient). These were mild and did not require discontinuation of treatment.

In the clotrimazole group, the adverse events were pruritus (one patient), burning (three patients), and epigastric pain after food (one patient). One patient had to be withdrawn from the study because she experienced increased symptoms, exudation and itching in the affected area.

There was no clinically significant change in the diastolic and systolic blood pressure and heart rate at end of the study as compared to baseline in either of the groups. There were no significant changes in laboratory values at the end of the study as compared to baseline.

Discussion

The efficacy of butenafine has been demonstrated in previous studies. In a study comparing butenafine 1% cream and vehicle in tinea cruris, the mycological cure rates were significantly higher with 2 weeks of once daily butenafine application. Four weeks post-treatment, P [;′V-0 the cure rates were 81 % and 13% for butenafine and vehicle respectively.[4] Butenafine has also been shown to be superior to vehicle in treatment of tinea corporis.[5] After 2 weeks of once daily application the mycological cure rates were 64% and 9% for butenafine and vehicle, respectively, which increased to 88% and 17% at 4 weeks after treatment cessation. Butenafine is effective in the treatment of tinea pedis when used twice daily for 1 week[6] or once daily for 4 weeks.[7]

The value of a newer agent is best judged in comparison with a standard, existing treatment. Topical azole antifungals are effective and have been used extensively for the treatment of dermatophytosis.[3] Our study compared butenafine and clotrimazole in the treatment of tinea cruris and tinea corporis and both compounds demonstrated high mycological cure rates. Butenafine showed a mycological cure rate of 90.90%, 95.45% and 90.9% after completion of therapy, 2 weeks after treatment cessation and at 4 weeks after treatment cessation, respectively while clotrimazole showed a mycological cure of 100%, 96.42% and 92.85% respectively after completion of therapy, two weeks after cessation of treatment and four weeks after cessation of treatment. Both treatment were equally effective. Relapse rates were similar in both groups.

An advantage with butenafine is the simpler requirement of a single daily application and a shorter period of two weeks compared to clotrimazole which requires twice daily application for 4 weeks. Clinical experience indicates that many patients do not complete the entire course of therapy because of rapid relief of symptoms and this results in a high rate of relapse. The reduced frequency of application and duration of treatment with butenafine may be expected to increase the compliance and reduce relapse rates.

Acknowledgement

This stusy was funded by Cipla Ltd.