A comparative randomized open label study to evaluate efficacy, safety and cost effectiveness between topical 2% sertaconazole and topical 1% butenafine in tinea infections of skin.

BACKGROUND: Dermatophytoses are the superficial fungal infections of skin, hair, and nail. Butenafine is a benzylamine group of antifungal that inhibits the biosynthesis of ergosterol by blocking squalene epoxidase. Sertaconazole is a newer imidazole antifungal which inhibits the biosynthesis of ergosterol by inhibiting 14-α lanosterol demethylase. The study was done to compare a newer antifungal with a relatively older one. AIM: To compare the efficacy, safety and cost effectiveness of topical 2% sertaconazole cream and 1% butenafine in tinea infections of skin.
MATERIALS AND METHODS: Patients were randomly allocated to two treatment groups. They were advised to apply the drug topically twice a day for one month on the lesions. They were followed up at an interval of 10 days. Clinical score and Global Evaluation Response were assessed at baseline and during each follow up.
RESULTS: A total 125 patients were recruited, out of them 111 completed the whole study. Median Sign and Symptom Score of tinea on the baseline was 9 [5,9] that was reduced to 0 [0,4] by 2% sertaconazole while it was 9 [6,9] in the butenafine group on the baseline that was reduced to 0 [0,6] at the end of the treatment. 98% and 90% of the patients got complete clearance of the lesions with butenafine and sertaconazole, respectively. Treatment with butenafine was more cost effective as compared to sertaconazole.
CONCLUSION: 1% butenafine is more efficacious, cost effective, and equally safe as compared to 2% sertaconazole in the tinea infections of skin.

RCT Entities:   Population Interventions Outcomes

What was known?

The imidazole antifungals are fungistatic while allylamine group agents are fungicidal. Fungicidal agents prevent relapse as compared to fungistatic agents.

Introduction

Dermatophytoses are fungal infections caused by three genera of fungi that have the unique ability to invade and multiply within keratinized tissue (hair, skin and nails).[1] Various systemic and topical antifungal agents are available for the treatment of dermatophytosis.[2] Butenafine is a benzylamine which are structurally related to allylamines. It exerts antifungal activity by blocking squalene epoxidation (catalyzed by squalene epoxidase), with resultant inhibition of ergosterol synthesis.[23] Contact dermatitis, erythema, irritation, and itching are the adverse reactions reported with butenafine.[3] Sertaconazole is an imidazole antifungal drug, which inhibits the fungal biosynthesis of ergosterol, by inhibiting the enzyme 14-α lanosterol demethylase.[3] Sertaconazole possesses both fungistatic and fungicidal activity depending upon its concentration.[45] It has anti- inflammatory activity also. Adverse events reported with sertaconazole are contact dermatitis, dry skin, application site reactions.[5] Sertaconazole is a newer antifungal agent as compared to butanafine. No, studies are done to compare the efficacy, safety, and cost effectiveness between these two agents in tinea infections of skin.

Aims and Objectives

Aims

To compare the efficacy, safety and cost effectiveness of topical 2% sertaconazole with topical 1% butenafine in tinea infections of skin.

Objectives

Primary objectives

Assessment of cure rate, Assessment of effectiveness of the treatments, Evaluation of safety.

Secondary objectives

Comparison of relapse rate with both the treatments, To identify and find the distribution of different species of tinea.

Materials and Methods

This study was registered with CTRI (Clinical Trial Registry of India) (CTRI/2012/06/002714). The study was approved by ethics committee of the teaching hospital. This was a prospective, randomized, open label, controlled, clinical study, conducted in patients attending the skin OPD of the teaching hospital, from June 2009 to January 2010. Diagnosis of tinea infections was done by the dermatologists.

Inclusion criteria

(1) Patients (New cases) from skin OPD having tinea infections of skin.

Exclusion criteria

(1) Follow up cases (2) pregnant or lactating women, (3) patients having allergy to topical imidazole or allylamine group of antifungal used in the study.

All the patients were approached and explained about the study. Written informed consent was taken from the each patient prior to the treatment.

Patients were allocated to both the treatment group in 1:1 ratio with alternate randomization. Group A: Received topical 2% sertaconazole cream to be applied twice a day for one month. Group B: Received topical 1% butenafine cream to be applied twice a day for one month. All patients were given oral chlorpheniramine maleate (4 mg) twice a day for a month for the relief of itching. 2% sertaconazole and 1% butenafine were purchased from the pharmacy store of the hospital. After clinical diagnosis, skin scraping was collected from the site of the lesion for mycological diagnosis.

Microscopy [Figures 1 and 2]

1-2 drops of 20% KOH (Potassium Hydroxide) were put on the skin scraping collected on the slide which was observed under 10x and 45x of the microscope.[16]

Fungal eliment (hyphe) in 20% KOH

Fungal eliment (hyphe) in 20% KOH

Culture [Figures 3-6]

Skin scraping was spread on plates of Sabouraud's agar supplemented with 1% Chloramphenicol to inhibit bacterial growth. The plates were packed air tight and incubated at 32-35o C in a special incubator for 7-10 days. They were seen at an interval of 3-4 days. Plates showing no growth at the end of four weeks were labeled as culture negative.[16]

E. Floccosum in sabauraudæs dextrose agar

T. mentagrophytes in sabauraudæs dextrose agar

T. rubrum in sabouraudæs dextrose agar

T. verrucossum in sabouraudæs dextrose agar

Identification of species [Figures 7-10]

Lactophenol cotton blue preparation (Sellotape) was used. These slides were seen under 10x and 45x. Species identification was done by the microbiologists on the basis of both gross as well as microscopic features. Photographs of both gross cultures and microscopic appearance of lactophenol cotton blue preparation were taken.

E. flocosum in lactophenol cotton blue preparation

T. mentagrophytes in lactophenol cotton blue preparation

T. rubrum in lactophenol cotton blue preparation

T. verrucossum in lactophenol cotton blue preparation

Patients were followed up at the interval of 10 day intervals. All the patients were followed up for 4 weeks after completion of the treatment to assess the relapse.

Outcome of the treatment was measured by two parameters:[78]

Clinical cure

Mycological cure.

Clinical cure

Three parameters Erythema; Pruritus - and Scaling each categorized into - Mild-1, Moderate-2, and Severe-3 were scored at baseline and during each follow up. Maximum score was 9.

Global Evaluation Response[67] was assessed at each follow up which is characterized as (1) Cleared: 100% remission of the clinical signs and symptoms except for residual manifestations (2) Excellent: 90-99% improvement of clinical signs and symptoms of baseline (3) Good: 50-89% improvement of clinical signs and symptoms of baseline (4) Fair: 25-49% improvement of clinical signs and symptoms of baseline (5) Poor: <25% improvement of clinical signs and symptoms of baseline (6) Worse: Clinical signs deteriorated from baseline

Mycological cure

When patients were cured clinically, skin scraping was taken and seen microscopically and cultured. When both KOH and culture were negative, if either of both positive before treatment were declared as mycologically cured.

Statistical analysis

nMaster 1.0 was used to calculate the sample size. Assuming the change in mean baseline sign and symptoms score with S.D. in the sertaconazole group to be 2 and the butenafine group to be 3 and estimated difference between two groups of 1 with alpha error set at the level of 5%, 50 subjects need to be recruited per arm. Considering dropout rate of 20%, total 125 subjects were recruited. Graph Pad Instat 3.0 was used for the statistical analysis. Normality of the data was checked by Kolmogorov Smirnov test. Mann Whitney test was used to compare the groups with respect to age. Fisher's exact test was used to find the difference in both the groups in terms of gender distribution as well as to assess the relapse rate. Baseline comparison of sign and symptom score between the groups was done by Mann Whitney Test. Total score of erythema, pruritus, and scaling before and after treatment was compared by Wilcoxon matched pairs signed rank test. Chi square test was used to compare global evaluation score at each follow up. P < 0.05 was considered as significant in all the statistical analysis.

Cost effectiveness

Cost effectiveness was calculated on the basis of total cost of medicines (topical agents plus antihistamines). Total amount of topical agents required was calculated by calculating FTU (finger tip units) (One finger tip unit is equal to 0.5 g. of topical agent, provided the lumen of the tube has diameter of 5 mm). Amount of topical agent needed was calculated by averaging requirement for different sites.[10] Cost of the topical agents was calculated by averaging the costs of all marketed preparations. Cost of the treatment was calculated accordingly for each follow up. Incremental cost (ΔC) = Cost of the new treatment – cost of the old treatment. Incremental effectiveness (ΔE) = efficacy of the new treatment- efficacy of old treatment.[9]

Results

A total 125 patients were enrolled for the study out of whom 5 patients from the sertaconazole group (Group A) and 9 patients from the butenafine group (group B) were lost to follow up. Finally, 111 patients completed the study.

Demographic characteristics

Median age in group A was 34[10,76] and in group B it was 35.(8,76) There was no difference between both the groups in age distribution (Mann–Whitney test; P value 0.53). There was a statistically significant difference between the groups in gender distribution (Fischer's exact test P value- 0.015).

Distribution of patients and species of tinea

Tinea corporis and cruris mixed infections was the most common diagnosis (27.92%) followed by tinea corporis (26.13%) [Table 1]. Most of the patients (86.48%) were suffering from severe tinea infection at the time of presentation. T. mentagrophytes (42.62%) was the most common species found followed by T. rubrum (24.59%) [Table 2].

Table 1

Distribution of patients according to diagnosis

Table 2

Distribution of tinea species between groups#*

Efficacy (Sign and symptom score)

Bothe groups were matched with respect to baseline sign and symptom score (Mann–Whitney test; P value: 0.068). Median Sign and Symptom Score of tinea at the baseline was 9 [5, 9] that was reduced to 0 [0, 4] by 2% sertaconazole while it was 9 [6, 9] in the butenafine group at the baseline that was reduced to 0 [0, 6] at the end of the treatment. Both were statistically significant. (Wilcoxon matched pair test, P < 0.001).

Efficacy (Global Evaluation Response)

On comparison of Global Evaluation Response at each follow up between both the groups by the Chi-square test [Table 3], there was a significant association between both the treatments at the first follow up (P 0.004. None of the treatments showed significant association at the second and third follow ups (P > 0.01).

Table 3

Global evaluation response at each follow up

Efficacy (Mycological cure) [Table 4]

Table 4

Relationship between KOH and culture

90% of the patients with sertaconazole and 97% of the patients with butenafine achieved mycological cure. There was a significant difference in mycological cure in both the groups individually (McNemar's test P=0.0001 for both the groups). But there was no difference between both the groups. Chi square test, P=0.29].

Safety of the therapy

No patient from either group complained of any application site or systemic adverse events during the course of treatment.

Relapse

No relapse was seen in the butenafine treatment group while three patients cured with sertaconazole relapsed at the end of 4 weeks surveillance period. There was no difference between both the groups in terms of relapse rate. (Fischer's exact test; P value 0.2482)

Total cost of therapy was more with sertaconazole as compared to butenafine treatment. The total cost of the treatment with 1% butenafine was 316.21, while it was 978.56 with 2% sertaconazole. Incremental cost (ΔC) was 662.35. Incremental effectiveness (ΔE) was 8%.

Discussion

Dermatophytoses (tinea) infections are one of the most common fungal infections of skin.[11] Results of the present study show that both butenafine and sertaconazole significantly reduced base line sign and symptom score. But global evaluation response showed more clearance of the lesion with butenafine at the end of treatment, which was also beneficial in preventing the relapse. Both the agents were found safe but butenafine was more cost-effective as compared to sertaconazole.

In the present study, most common age group infected with tinea infections was 11-30 years. The male female ratio was 3.44:1. Tinea cruris and corporis mixed infection (27.93%) was the most common diagnosis. Sen et al.[12] have reported male: female ratio 2.85: 1. The most common age group in their study was 21-30 years (44%) and the most common type of lesion reported by them was tinea corporis (48%). T. mentagrophyte (42.62%) was the most common species found in the present study followed by T. rubrum (24.59%) which contradicts a study by Kannan et al. who have found T. rubrum (70.83%) to be the most common isolate followed by T. mentagrophytes (16.7%).[13]

Our study shows that 90% of the patients were completely cleared of the lesion clinically at the end of treatment with sertaconazole. Mycological cure was achieved in 90% of the patients. A study by Sharma et al., has shown that sertaconazole produced 62.3% clearance at the end of 2 weeks.[14] In the study by Alomar et al., 95.6% clinical cure rate was seen at the end of treatment with sertaconazole[15] This study demonstrated that 62.74% of the patients were completely cleared with the lesion clinically at the end of 2nd follow up (20 days) and 98% at 3rd follow up (30 days) with topical 1% butenafine cream. 97% of the patients achieved mycological cure at the end of treatment. Tschen et al. have reported that 40% of the patients showing mycological cure after 1st week and 88% of the patients after 4 weeks with 1% butenafine cream.[16] The present study reported that no patient complained of any administration site or systemic adverse events during treatment with both the agents. Side effects reported with butenafine in the study by Rammam et al. were burning (two patients), pruritus (two patients), striae (one patient), and erythema with atropy (one patient) which were mild in intensity.[17] Sharma et al. have reported five patients in the sertaconazole group and nine in the miconazole group developing mild to moderate adverse events.[14] The present study shows that no patient treated with butenafine relapsed while three patients relapsed from sertaconazole treatment. However, there was no statistically significant difference between both the groups in relapse rate (P > 0.05). Lesher Jr et al. have concluded that as butenafine provided residual protection for 4 weeks, no relapse was seen.[18] Cost-effective analysis of the present study showed treatment with butenafine cheaper as compared to sertaconazole. Results of this study are comparable to other studies however some observer bias may have occurred unintentionally.

Conclusion

1% butenafine is more efficacious, cost effective, and equally safe as compared to 2% sertaconazole in tinea infection of skin. It also provides residual protection which may prevent the relapse. Fungicidal agents should be preferred over fungistatic agents in the treatment of superficial fungal infections (tinea) to prevent the relapse. Cost should also be considered as a factor in the choice of an antifungal.

What is new?

Butenafine is more efficacious, safe as well as cost effective as compared to a relatively newer imidazole antifungal, sertaconazole in tinea infections of skin.