PEDIATRICS Vol. 109 No. 4 April 2002, pp. 602-607
Terbinafine in the Treatment of Trichophyton Tinea Capitis: A Randomized, Double-Blind, Parallel-Group, Duration-Finding Study
* University of California, San Diego, California
University of California, San Francisco, California
Hospital for Sick Children, Toronto, Ontario, Canada
|| Rainbow Babies and Children’s Hospital, Cleveland, Ohio
¶ Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
# Midwest Cutaneous Research Corporation, Clinton Township, Michigan
** Dermatology Research Associates, Cincinnati, Ohio
University of Toronto, Toronto, Ontario, Canada
Novartis Pharmaceutical Corporation, East Hanover, New Jersey
|||| Novartis Pharma AG, Basel, Switzerland
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Objectives. Terbinafine has been shown to be effective in tinea capitis, using different treatment durations. However, no direct comparison of treatment duration has previously been investigated. This randomized, double-blind, parallel-group, multicenter study was designed to assess the effect of terbinafine treatment duration on the outcome of Trichophyton tinea capitis in a North American population.
Methods. A total of 176 patients with a clinical diagnosis of tinea capitis were enrolled in this study and treated with oral terbinafine (3–6 mg/kg/d) for 1, 2, or 4 weeks. All patients were to be followed until week 12. A total of 159 patients had culture-confirmed tinea capitis attributable to Trichophyton species and constituted the intent-to-treat population used for efficacy analysis (50, 55, and 54 patients in the 1-, 2-, and 4-week arms, respectively).
Results. At the end of study, effective treatment, defined as negative culture and low scores on signs and symptoms, was achieved in 56%, 69%, and 65% of patients who were treated with terbinafine for 1, 2, and 4 weeks, respectively. A negative culture was achieved in 60%, 76%, and 72%, respectively. Overall, the efficacy data showed that both the 2- and 4-week treatment regimens are clinically superior to the 1-week regimen. Terbinafine was well tolerated, and the incidence of adverse events showed no relationship to the duration of therapy.
Conclusion. When efficacy, cost, and compliance are taken into consideration, 2 weeks of terbinafine therapy appears to be the optimal treatment duration for patients with Trichophyton tonsurans tinea capitis.
Key Words: Tinea capitis • Trichophyton species • terbinafine
Abbreviations: TSSS, total signs and symptoms score • AE, adverse event • ITT, intent-to-treat
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Tinea capitis, primarily a disease of children,1,2 is a public health problem in some countries because of increased incidence and epidemic transmission. From 1984 to 1993, the incidence of tinea capitis increased by 84% in California.3
At present, the standard treatment of tinea capitis is oral griseofulvin, 15 to 20 mg/kg daily for approximately 6 to 8 weeks, although longer duration may be needed, as clinical response is highly variable. Compliance with such a lengthy treatment regimen is poor, and, in addition, a pediatric formulation of griseofulvin (suspension) is not available in many countries. Furthermore, some patients do not respond to standard therapy and may require higher doses or prolonged durations. In a recent survey of griseofulvin treatment of tinea capitis in a practice setting, approximately 40% of patients did not respond to the drug and required additional treatment.4 The goal of a new therapy for tinea capitis would be to reduce treatment duration while maintaining good efficacy and safety profiles.5–7
Comparative studies between terbinafine and griseofulvin have indicated that treatment with terbinafine for 4 weeks is at least as effective as griseofulvin for 8 weeks.8–11 Other studies have examined the relationship between clinical efficacy of terbinafine in tinea capitis and the duration of treatment (4 weeks or less).12–14 However, these investigations were conducted in countries outside North America and involved study populations that were infected with both Trichophyton and Microsporum species. Recently, an open-label study conducted in Canada showed that a 2-week terbinafine treatment course was highly efficacious in children with tinea capitis.15
The aim of this study was to assess the effect of terbinafine treatment duration on the outcome of tinea capitis caused by Trichophyton species in a North American population.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Patient Population
This randomized, placebo-controlled trial was conducted in 11 United States and 3 Canadian clinical centers. The study was performed in accordance with the guidelines laid down by the Declaration of Helsinki.
Patients were aged 4 years or older (98% patients <18 years old; mean age, 7.4 years) and healthy apart from their tinea capitis infections. Tinea capitis was diagnosed clinically and confirmed by positive culture for Trichophyton species (T tonsurans, 98.74%; T soudanense, 0.63%; T verrucosum, 0.63%). When all entry criteria were met, patients were permitted to start study medication while awaiting the culture result and were discontinued from the study when the culture result was negative or revealed a non-Trichophyton species. Written consent was obtained from patients or parents/legal guardians of younger patients and from children themselves who were considered to be of the age of reason. Women of childbearing potential were required to use a medically approved method of contraception during the study.
Indications and main criteria for inclusion were male and female patients, aged 4 years or older, with clinically diagnosed tinea capitis caused by Trichophyton species.
Reasons for exclusion were 1) any systemic treatment for tinea capitis in the month before enrollment or topical treatment in the week before enrollment; 2) kerions that required immediate treatment, concurrent seborrheic dermatitis, or other scalp conditions such as scabies, head lice, psoriasis, or atopic dermatitis; 3) immunocompromised patients or a history of malignancy within 5 years; 4) chronic or active liver disease; 5) serious gastrointestinal disease; 6) hypersensitivity to terbinafine or placebo; 7) treatment with any other investigative agent within the previous 8 weeks; and 8) pregnancy or lactation.
Study Design and Interventions
The study consisted of a 4-week double-blind treatment phase and an 8-week double-blind follow-up phase. After baseline evaluations, patients were randomly assigned to 1 of 3 treatment arms using a 1:1:1 ratio (terbinafine for 1, 2, or 4 weeks followed as appropriate by placebo).
Daily doses of terbinafine were based on body weight: 62.5 mg/d for <20 kg, 125 mg/d for 20 to 40 kg, and 250 mg/d for >40 kg. Terbinafine was provided as standard 125-mg and 250-mg tablets, with the 125-mg tablets scored for halving. Identically matched placebo tablets were supplied for each of the 2 terbinafine dosage strengths. Patients were instructed to take the medication at approximately the same time every day, with a liquid or semisolid food. For assessing compliance, patients were asked to return unused medication at each visit.
The investigator, the study personnel, the patient, and parent/guardian were blinded with respect to terbinafine treatment duration of each patient.
Patients were advised not to use hair care products used by other family members and to avoid chemical or heat hair treatments, such as permanents and coloring, for the duration of the trial. They were supplied with a nonmedicated shampoo and instructed to use this agent, for scalp cleaning, twice weekly. Whenever possible, family members were checked for the presence of tinea capitis infection and cultures were obtained from family members.
Evaluations
Patients were scheduled for clinic visits at the end of weeks 1, 2, and 4 of active treatment and at weeks 8 and 12 of the follow-up phase. Efficacy assessments (clinical examination, microscopy, and culture) were conducted at the initial visit and every visit thereafter. Microscopy was performed at each study site, whereas culture specimens were sent to a central laboratory. The severity of 5 different signs and symptoms (erythema, desquamation/scaling, papules, pustules, and pruritus) was rated on a 4-point scale (0, absent; 1, mild; 2, moderate; 3, severe). These were summed for each patient at each assessment point to obtain a Total Signs and Symptoms Score (TSSS), with a maximum value of 15 points.
The primary efficacy variable was complete cure at end of study. Complete cure was defined as negative culture and a TSSS of 0. Secondary efficacy variables were effective treatment defined as a negative culture and a TSSS 
2 or less, with no individual symptom score >1; clinical cure was defined as a TSSS of 0, and mycological cure was defined as negative microscopy and negative culture.
For investigating the dose-response relationship, an analysis of the daily dose of terbinafine received per body weight by each patient was performed. Safety and tolerability evaluations included adverse event (AE) reports; physical examinations and vital signs (at baseline and at week 4); and regular monitoring of hematology, blood chemistry, and urinalysis, with samples sent to a central laboratory (baseline and weeks 2, 4, and 12). At the final scheduled visit or at the time of early discontinuation, patients or their parents/guardians rated the tolerability of their assigned treatment as very good, good, moderate, poor, or very poor.
Statistical Methods
The primary efficacy outcome, complete cure at the end of study, was ascribed using data from the last postbaseline, nonmissing clinical evaluation. Between-group differences in the primary and secondary efficacy outcome measures were tested in a 2-stage procedure using data obtained at each visit and at the end of study. The first stage was a Cochran-Armitage Trend Test with a 2-sided 5% level of significance. When at least 1 between-group difference was significant, 3 pairwise comparisons were made using the Cochran-Mantel-Haenszel test (2-sided 
of 0.05) and the Breslow-Day test (2-sided of 0.10). As this was a phase II trial, no adjustment in the level was made for multiple comparisons.
The safety analysis included all patients who received at least 1 dose of study medication and had at least 1 postbaseline safety assessment. The primary efficacy analysis was conducted on the intent-to-treat (ITT) population, consisting of all patients who received at least 1 dose of study medication, had at least 1 postbaseline efficacy assessment, and had a positive screening culture for Trichophyton species.
A study population of 120 evaluable patients (40 in each arm) was determined on the basis of the following assumptions: for a projected 50% complete cure rate in the arm receiving terbinafine for 2 weeks, 40 patients in each arm would provide 76% power to detect a trend ranging from <35% to >65% for the other 2 treatment durations.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The distribution of patients is shown in Fig 1. Of 177 patients randomized to double-blind treatment, 176 (99%) were included in the safety analysis. A total of 9 patients (5.1%) had a screening culture negative for Trichophyton species and were therefore not included in the ITT population used for efficacy analysis. Forty-one patients (23%) discontinued randomized treatment for various reasons, most commonly as a result of loss to follow-up (n = 18), withdrawal of consent (n = 9), and protocol violation (n = 8). Four patients discontinued for lack of efficacy, 1 because of an AE and 1 who no longer required the study drug. Reasons for discontinuation did not differ among the 3 treatment arms.
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Patients’ demographics are summarized in Table 1. The 3 treatment groups were comparable at baseline in all respects. The majority of patients (87%) were black; males slightly outnumbered females (57.2% males), and the mean age was 7.4 years. Only 3 adult patients were enrolled in this study. T tonsurans was the cause of all but 2 of the infections, which were caused by T soudanense and T violaceum.
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Patients’ disease characteristics, as assessed by medical history, are shown in Table 2. Approximately 25% of patients had experienced a previous tinea capitis infection. The duration of the present infection was >16 weeks for approximately 45% of patients, and >60% had at least 1 other family member affected by the disease.
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Treatment Efficacy
At the end of study, complete cure was observed in approximately 50% of the ITT population (Table 3). In all groups, complete cure rates continued to increase over the 12 weeks of observation (Fig 2). There was a trend toward higher complete-cure rates with increasing duration of terbinafine treatment, but these differences were not statistically significant.
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Secondary outcome variables, summarized in Table 3, suggest some advantage for the 2- and 4-week treatment regimens. Overall, approximately two thirds of the patients achieved effective treatment (mycological cure, with TSSS
2), clinical cure (TSSS of 0), and mycological cure (negative culture and microscopy). The difference in mycological cure at the end of the study between terbinafine treatment for 1 week and 2 weeks was of borderline statistical significance (P = .051) in favor of terbinafine treatment for 2 weeks. All of the individual signs and symptoms of tinea capitis were reduced in frequency and severity in all treatment groups during the course of the trial. The number and percentage of patients by category of TSSS are given in Table 4. There was no difference in mycological cure rates in patients with family members affected by tinea capitis infection (n = 84) compared with patients without affected family members (n = 75). The rates in the former group were 48.3% for the 1-week treatment arm, 77.8% in the 2-week treatment arm, and 60.7% in the 3-week treatment arm. The rates in the latter group were 57.1%, 60.7%, and 61.5%, respectively.
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Most patients received daily doses of terbinafine between 3 and 6 mg/kg/d depending on their body weight. The effect of terbinafine daily dose per body weight on the main efficacy parameters is presented in Table 5. Patients who received terbinafine daily dose of >4.5 mg/kg/d experienced higher clinical and mycological responses compared with those who received a daily dose of 4.5 mg/kg/d or less, irrespective of treatment duration. The higher cure rate in patients who received higher doses of terbinafine was evident for all efficacy parameters.
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Safety and Tolerability
Approximately 44% of patients experienced AEs during the study. The majority of AEs were assessed by investigators as mild to moderate and unlikely to be related to study medication. The most frequent AEs included upper respiratory tract infections, gastrointestinal upsets, and other events common in this patient population. The overall rate of AEs did not differ between treatment groups.
One serious AE (sickle cell crisis) was reported on week 10 of the study in an 8-year-old child from the 1-week arm. This AE was assessed as severe but not related to study medication. The patient recovered within 1 week and completed the study. One patient in the 1-week arm discontinued because of an AE (tinea corporis on the right eyebrow and arm) at the completion of week 4. This event was assessed as mild and not related to study medication.
Six patients reported 8 AEs possibly related to study medication. Five of these events were gastrointestinal (abdominal pain, nausea, increased appetite, discolored feces, and flatulence). The remainder were headache, hyperesthesia, and leukopenia. Gastrointestinal disorders and headache are among the labeled side effects of terbinafine. Moderate scalp hyperesthesia occurred at week 6 in a patient who had received terbinafine for 4 weeks, and resolved by the following week. A patient in the 4-week group had transient, moderate leukopenia beginning at week 2 and remaining at a similar level at week 4 (ie, 3 x 109/L), which resolved as the study progressed (4.8 x 109/L at week 12). Evaluation of laboratory parameters identified no clinically significant change from baseline in biochemistry (liver enzymes) or urinalysis results in any of the treatment groups.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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This is the largest multicenter, randomized, double-blind study conducted to date in children with tinea capitis. Oral terbinafine was well tolerated and showed efficacy in the treatment of tinea capitis. Terbinafine therapy for 1 week was least effective and resulted in the lowest frequency of favorable results for all outcome parameters studied: complete cure, clinical cure, and mycological cure. For the secondary efficacy assessments, the 2-week treatment group had a greater percentage of patients who achieved mycological cure and effective treatment. Differences between treatment groups in the rate of complete cure at end of study, the primary efficacy variable, were smaller than anticipated, leading to insufficient statistical power to discriminate between the treatment durations tested. Therefore, small differences in treatment success between the 2-week and the 4-week groups could not have been detected by this study. The rates of clinical and mycological cure were comparable to those reported in the literature with terbinafine or griseofulvin used for various durations.8–16 However, direct comparison with previous studies should be made with caution in view of the stringent cure criteria defined by this study.
Approximately one third of patients failed to achieve mycological cure after treatment with terbinafine for 2 or 4 weeks. There may be several explanations for this. First, compliance, even with short drug regimens, may be a problem in the patient population studied, and >10% of patients were lost to follow-up despite careful efforts to improve patient compliance and attendance at clinic visits. Second, a high percentage of family members also had the disease or were asymptomatic carriers. Unfortunately, it was not possible to culture for Trichophyton infection systematically among family members in this study, and thus the prevalence of asymptomatic carriers and affected family members should be interpreted with caution as it may represent an underestimation. It is recognized that careful attention should be paid to the treatment of family members in clinical practice. Third, clearance of terbinafine is approximately 40% higher in children compared with adults,17 and one can hypothesize that higher doses may be necessary in some refractory cases. This is further supported by the dose-response analysis that showed lower cure rates for the patients who received a daily dose of terbinafine of 4.5 mg/kg/d or less, independent of treatment duration. Future research into the treatment of tinea capitis should favor large, multicenter trials with long-term follow-up of patients to determine more precisely the true effect of treatment. However, tinea capitis infection is difficult to study, and long-term follow-up of patients can be problematic.
In this mainly pediatric population, oral terbinafine was well tolerated. Most of the AEs reported were mild or moderate in severity, and the few suspected to be treatment related were in accordance with the known safety profile of oral terbinafine. The only serious AE that occurred, a sickle cell crisis, did not result in discontinuation from the study. It occurred after therapy was complete and was associated with a chest infection. One patient withdrew from medication because of a tinea corporis infection. There were no significant differences in AEs between treatment groups and no clinically significant abnormalities in laboratory parameters except for 1 case of transient leukopenia.
Treatment with terbinafine, for either 2 or 4 weeks, seems to be effective in two thirds of patients with Trichophyton tinea capitis, a disease that requires longer treatment duration with griseofulvin, the current standard therapy. In clinical practice, early treatment of affected family members, as well as combination with topical treatment, should help to optimize the cure rates. Adjunctive therapy with selenium sulfide or other topical antifungal shampoo twice weekly may help to decrease shedding of viable fungal organisms during treatment and thus hasten response and prevent spread of the disease.18,19 In view of the well-recognized compliance problems in the patient population afflicted with tinea capitis, a 2- or 4-week period of systemic terbinafine therapy is a therapeutic alternative that is more attractive than standard prolonged griseofulvin treatment. Additional studies to investigate the pharmacokinetics and effect of increased terbinafine dosing, as well as comparative trials with griseofulvin, will be extremely useful in determining the optimal therapy for tinea capitis.
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ACKNOWLEDGMENTS |
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This study was supported by an educational grant from Novartis Pharma AG.
The Tinea Capitis Study Group consisted of J. Connor, University of California, San Diego, California; E. Quintal, Quintal Medical Center, New Orleans, Louisiana; J. Powel, Hospital Sainte Justine, Montreal, Canada; A. Pandya, Southwest Medical Center at Dallas, Dallas, Texas; D. Hogan, LSU Medical Center, Shreveport, Louisiana; R. Chesney, Le Bonheur Children’s Medical Center, Memphis, Tennessee; and A. Mastropolo, G. Hoexter, and H. WernerSchlenzka, Novartis Pharma AG, Basel, Switzerland.
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FOOTNOTES |
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Received for publication Jul 11, 2001; Accepted Oct 31, 2001.
Reprint requests to (S.F.F.) School of Medicine and Children’s Hospital, University of California San Diego, 3030 Children’s Way, Suite 408, San Diego, CA 92123-4228. E-mail: sfriedlander{at}chsd.org
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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