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332 A. Singal et al. A fungal culture was also performed in all patients but a positive culture was not a prerequisite for inclusion in the study. Pregnant and lactating females, patients with extensive (w 20% of skin surface) tinea, concurrent skin diseases which could interfere with the clinical evaluation on subsequent visits, or with other severe systemic diseases were excluded from the study. Patients with a history of treatment with other oral or topical antifungal drugs in the previous 4 weeks or with known hypersensitivity to allyalamines/imidazoles were also excluded. Eligible patients were randomized to receive either butenafine (applied once daily for 2 weeks) or clotrimazole cream (twice daily application for 4 weeks) in a doubleblind manner. Individual drugs were dispensed in two identical containers of 5 g capacity for morning and evening application. As butenafine was to be applied once daily for 2 weeks, a placebo (vehicle) was supplied in a similar container for evening application for the initial 2 weeks and for twice daily application for the next 2 weeks. For both groups, neither the investigators nor the patients were aware of the composition of the drugs allocated. A clinical nurse had the codes for the drugs, which were revealed only after completion of the study. At the initial visit, all the study patients underwent detailed physical and cutaneous examination. All clinical details were recorded on a predesigned proforma. The symptoms and signs like erythema, scaling and pruritus were designated a scale of 0 to 3 as follows: 05 none, 15 mild, 25moderate and 35severe. The individual symptom scores were added and a total score (clinical assessment score) was recorded, with a maximum additive score of 9. Lesional skin scraping in 10% KOH was performed to confirm the presence of hyphae. Fungal culture was done on Sebourauds dextrose agar medium to identify the fungal species. Laboratory tests including complete haemogram, liver and kidney function tests, random blood sugar and urine microscopy were done at the initial visit. Patients were followed up after 1, 2, 4 and finally 8 weeks (4 weeks after the cessation of treatment). At each visit, clinical examination was carried out, clinical assessment score was calculated and KOH

smear was repeated. Fungal culture was repeated at the second and fourth week. Blood tests were repeated at the fourth week and whenever required. Adverse effects, if any, were recorded at each visit.

Table II. Profile of lesions among study population (total580).Clinical cure was defined as a

clinical assessment score of 0 or 1 at any time during the 8-week study period. Mycological cure was defined as a negative KOH smear at any follow-up visit. Relapse was defined as a positive KOH smear at any point till 8 weeks, once it had become negative during the treatment. 2Results were analysed as per protocol. The p value was calculated using the xtest and/or unpaired t test as appropriate. The level of significance was set to 0.05.

Results Eighty patients fulfilled the inclusion criteria during the study period. Each patient was randomized to either the butenafine or the clotrimazole group based on random tables. The baseline characteristics of the patients were comparable (Table I). Twelve (30%) patients had a history of similar lesions in the past in the same season and 11 (27.5%) patients had at least one family member with similar skin lesions, probably due to sharing of towels and clothes and the hot and humid

environment. In all, 50% of the patients included in the study had tinea corporis and 28.8% had both tinea corporis and cruris infection simultaneously. Details of patients with different types of lesions in both the treatment groups are provided in Table II. In the butenafine group, of the 40 patients recruited at baseline, 34, 31, 27 and 20 patients were followed up after 1, 2, 4 and 8 weeks, while in the clotrimazole group 34, 32, 25 and 21 patients were followed at similar intervals. Others were lost to followup. Clinical assessment score was calculated in both the treatment groups on all visits and mean score was calculated at each time point. With treatment the score declined significantly in both the treatment groups (Table III). In the butenafine

Table I. Baseline characteristics of patients in two treatment groups. Characteristics Butenafine (n540) Clotrimazole (n540) Males 30 (75%) 23 (57.5%) 3.68 3.92Females 10 (25%) 17 (42.5%) Age (years) 28.7 10.46 29.311.52 KOH-positive 40 (100%) 40 (100%) Positive culture 18 (45%) 20 (50%) Mean duration of disease (weeks)

Type of dermatophytosis Number of patients (% of total) Butenafine (n540) Clotrimazole (n540) T. cruris 17 (21.25) 10 7 T. corporis 40 (50) 18 22 T. cruris + T. corporis 23 (28.75) 12 11

Butenafine and clotrimazole in tinea cruris and corporis 333 group, the mean score declined from 6.65 1.29 at baseline to 2.85 0.78 at week 1, 1.00 0.63 at week 2, 0.56 0.51 at week 4, and 0.65 0.49 at week 8 (Figure 1). The mean reduction in the clinical assessment score from baseline was 5.90 1.04 at 2 weeks and 6.56 1.12 at 4 weeks. In the clotrimazole group, the score reduced from a mean of 6.45 1.28 at baseline to 3.12 0.84 at week 1, 1.50 0.72 at week 2, 0.76 0.52 at week 4 and 0.62 0.50 at week 8 (Figure 1). The mean reduction in the clinical assessment score from baseline at 2 weeks was 5.00 1.08 and at 4 weeks was 5.56 1.12. The clinical assessment score in the butenafine group was significantly less as compared with the clotrimazole group at the end of 2 weeks of treatment (1.0 0.63 in the butenafine group and 1.5 0.72 in the clotrimazole group, p50.005); however, at the end of 4 weeks it became

Table III. Clinical assessment score.comparable

in the two treatment groups (0.56 0.51 in butenafine group and 0.76 0.50 in clotrimazole group, p5 0.158) (Table III). The reduction in the clinical assessment score at 2 weeks as well as 4 weeks was significantly more in the butenafine group than in the clotrimazole group (p5 0.001 at 2 weeks and 0.002 at 4 weeks) (Table IV). The number of patients achieving clinical cure after treatment for 1 week and 2 weeks was significantly more in the butenafine group. However, this became statistically comparable at 4 as well as 8 weeks (Table V). Similiarly, significantly more patients treated with butenafine achieved mycological cure after treatment for 1 week; however, the number of patients achieving mycological cure became comparable after 4 weeks (Table VI). Eighteen patients in the butenafine group and 20 in the clotrimazole group had a positive fungal culture at baseline. All cultures were negative at 2

Post treatment Pretreatment2 wks 4 wks 8 wks Butenafine 6.651.29 (40) 1.00.63 (31) 0.560.51 (27) 0.650.49 (20) Clotrimazole 6.451.28 (40) 1.50.72 (32) 0.760.52 (25) 0.620.50 (21) p value 0.489 0.005 0.158 0.842

334 A. Singal et al.

Table IV. Reduction in clinical assessment score with treatment. Week 2 Week 4 DrugNumber of patients Change in score* Number of patients Change in score** Butenafine 31 5.90 1.04 27 6.56 1.12 Clotrimazole 32 5.00 1.08 25 5.56 1.12 Butenafine vs clotrimazole *p value50.001, **p value50.002. Table VI. Mycological cure. Butenafine (%) Clotrimazole(%) p value 1 week 21/34 (61.7) 6/34 (17.6) 0.000

and 4 weeks in the butenafine group; however, three patients were culture-positive in the clotrimazole group at 2 weeks and one at 4 weeks. T. rubrum was the most commonly isolated dermatophyte, grown in 29 of 38 isolates (76.3%), followed by E. floccosum in 7 (18.4%) and T. mentagrophytes in 2 (5.3%). In the butenafine group, relapse was not observed in any patient, while two patients in the clotrimazole group became KOH-positive again at 8 weeks and one of them also had evidence of clinical relapse. Two of 37 patients complained of transient burning sensation at the application site in the butenafine group in the first week but it resolved spontaneously while on treatment and did not require discontinuation of therapy. In the clotrimazole group, two patients complained of increased pruritus and two had mild increase in the lesional erythema and scaling during the first week of application. There was no biochemical or haematological alteration in any patient in either of the groups. Discussion The efficacy of butenafine has not been compared with the established topical therapeutic agents like clotrimazole. The clinical cure rate (26.5% vs 2.9%) as well as the mycological cure rate (61.7% vs 17.6%) was significantly higher in the butenafine then in the clotrimazole group at 1 week (Tables V and VI). At follow-up in subsequent weeks the mycological cure rates were again higher with
Table V. Clinical cure. Butenafine (%) Clotrimazole(%) p value 1 week 9/34 (26.5) 1/34 (2.9) 0.000 2 weeks 24/31 (77.4) 18/32 (56.2) 0.006 4 weeks 26/27 (96.2) 24/25 (96.0) 0.735 8 weeks 20/20 (100) 20/21 (95.2) 0.512

2 weeks 30/31 (96.7) 26/32 (81.2) 0.057 4 weeks 26/27 (96.2) 23/25 (92.0) 0.471 8 weeks 20/20 (100) 20/21 (95.2) 0.512butenafine; however, the

difference was not statistically significant (96.7% vs 81.2%, 96.2% vs 92%, 100% vs 95.2% at weeks 2, 4 and 8, respectively (Table V). Thus butenafine achieved faster mycological cure, although cure rates were comparable at 4 weeks. The clinical assessment score was also significantly lower with butenafine as compared with clotrimazole at week 2 (Table III). The clinical assessment score from baseline improved significantly more with butenafine at both weeks 2 and 4 (Table IV). This is because the fungicidal activity of butenafine (7) leads to rapid resolution of clinical signs and symptoms, while clotrimazole is only a fungistatic drug (3). The efficacy of topical 1% butenafine in the treatment of superficial fungal infections has been demonstrated in many studies. Butenafine was better than vehicle in treating interdigital tinea pedis (8) as well as tinea corporis (9). Butenafine recipients had significantly higher rates of mycological cure at day 7 (64% vs 9%) with continued improvement through day 42 (88% vs 17%) (9) The results of another vehicle-controlled, double-blind, randomized, parallel study indicate that 1% butenafine applied once

daily for 2 weeks is safe and effective in the treatment of tinea cruris and the proportion of patients cured increased between the end of treatment and 4 weeks post treatment (5). Following antimycotic treatment, tinea infections often recur or relapse because patients often discontinue therapy prematurely as their symptoms abate before mycological cure is achieved, and some drugs may only suppress the growth of the pathogen rather than fully eradicate it (7,10). Butenafine may have the potential to overcome these barriers, because of the faster mycological cure, as seen in the present study. There was no relapse for at least 4 weeks after the cessation of therapy; this is because butenafine demonstrates a reservoir effect in the skin even after elimination of the fungi (7). Thus single daily application, faster relief of symptoms, shorter durations of therapy, a favourable safety profile and absence of relapse make butenafine a preferred therapeutic modality as compared with clotrimazole for superficial dermatophytosis. References
1. Crissey JT. Common dermatophyte infections: a simple diagnostic test and current management. Postgrad Med. 1998;103:1912.

Butenafine and clotrimazole in tinea cruris and corporis 335

2. Pierard GE, Arrese JE, Pierard-Franchimont C. Treatment and prophylaxis of tinea infections. Drugs. 1996;52:20924. 3. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol. 1993;28:S28 S34. 4. McNeely W, Spencer CM. Butenafine. Drugs. 1998;55: 40512. 5. Lesher JL Jr, Babel DE, Stewart DM, Jones TM, Kaminester L, Goldman M, et al. Butenafine 1% cream in the treatment of tinea cruris: a multicenter, vehiclecontrolled, double-blind trial. J Am Acad Deramatol. 1997;36:S20S24. 6. Arika J, Hase J, Yokoo M. Antitrichophyton mentagrophytes activity and percutaneous permeation of butenafine in guinea pigs. Antimicrob Agents Chemother. 1993;37:3635.

7. Arika T, Yokoo M, Hase T, Maeda T, Amemiya K, Yamaguchi H. Effects of butenafine hydrochloride, a newbenzylamine derivative, on experimental dermatophytosis in guinea pigs. Antimicrob Agents Chemother. 1990;34: 22503. 8. Savin R, De Villez RL, Elewski B, Hong S, Jones T, Lucky A, et al. One-week therapy with twice-daily butenafine 1% cream versus vehicle in the treatment of tinea pedis: a multicenter, double-blind trial. J Am Acad Dermatol. 1997;36: S15S19. 9. Greer DL, Weiss J, Rodriguez DA, Hebert AA, Swinehart JM. A randomized trial to assess once-daily topical treatment of tinea corporis with butenafine, a new antifungal agent. J Am Acad Dermatol. 1997;37:2315. 10. Berman B, Ellis C, Leyden J, Lowe N, Savin R, Shupack J. Efficacy of a 1-week twice-daily regimen of terbinafine 1% cream in the treatment of interdigital tinea pedis. J Am Acad Dermatol. 1992;26:95660.