Efficacy of Terbinafine for Toenail Onychomycosis

Abstract

The efficacy of terbinafine (250 mg/day) in the treatment of toenail onychomycosis was evaluated in a large open-label, multicenter trial of 12, 18, and 24 weeks of therapy. All 1,534 patients had onychomycosis, confirmed by either positive potassium hydroxide (KOH) wet mount, positive fungal culture, or both, and all received at least 12 weeks of treatment. Treatment was continued for an additional 6 or 12 weeks, depending on the extent of the disease at follow-up. Mycologic cure rates (negative culture plus negative KOH) at week 72 were 72.1% in the 12-week treatment group, 72.5% in the 18-week group, and 77.0% in the 24-week group. In all groups, clinical cure rates were higher at week 72 than at week 48: 49.5% of the 12-week group, 49.2% of the 18-week group, and 44.6% of the 24-week group experienced clinical cure by the end of the study. Both mycologic and clinical recurrence rates were low in all treatment groups at the 72-week assessment. The results of this study confirm the efficacy of terbinafine in the treatment of toenail onychomycosis as demonstrated in previous registration and large-scale clinical trials.

Onychomycosis, probably the most common of all nail disorders, accounts for approximately 50% of all nail problems. Recent decades have seen a substantial increase in the number of patients who suffer from mycotic nail disorders. Several factors may be responsible for this increase, including a rise in medical conditions contributing to immunodeficiency and greater use of systemic antibiotics, invasive surgery, and immunosuppressive therapies. [1]

From a clinical perspective, it is important to keep in mind that onychomycosis presents more than cosmetic annoyance. Some patients may find it difficult to remain on their feet for extended periods; others may be embarrassed enough about the appearance of their nails to avoid social interactions in which their feet may be visible. Fungi from the nail may also spread to adjacent or distant sites, leading to further compromise in quality of life. [1]

The vast majority of pathogens involved in onychomycosis are dermatophytes, particularly Trichophyton rubrum. A Canadian survey of the causative organisms in 4,000 patients with fungal nail infections found that only 3.3% of the fungal isolates were non-dermatophytic molds and 5.5% of all isolates were Candida species. [2] There were similar findings in the previously published epidemiologic analysis of the causative organisms in the present study. Of the culture-positive isolates grown from nail samples, 91.3% were dermatophytes, with the most common being T rubrum (97.4%). Other dermatophytes were Trichophyton mentagrophytes (2.4%), Trichophyton tonsurans (0.1%), and Epidermophyton floccosum (0.1%). Yeasts and nondermatophytic molds accounted for only a small percentage of the isolates. [3]

Terbinafine is the first allylamine antifungal drug intended for oral use. It inhibits squalene epoxidase, a complex, membranebound enzyme involved in the synthesis of the fungal cell membrane. [4] The resulting accumulation of squalene contributes to the fungicidal activity of terbinafine in vitro against dermatophytic pathogens.

Clinical studies of 12 weeks of therapy with terbinafine for toenail onychomycosis have demonstrated mycologic cure rates at the end of follow-up of 81% (week 52) [5] and 73% (week 48). [6] The present study was conducted to determine whether terbinafine therapy for longer durations will increase cure rates in difficult-to-treat onychomycotic infections, particularly those involving more than 50% of the great toenail.

The primary objective was to determine the efficacy and safety of 12, 18, or 24 weeks of continuous therapy with 250 mg/day of terbinafine. The secondary objective was to evaluate the impact of terbinafine treatment on the quality of life of patients with onychomycosis of the toenails. Previously published data from this study have confirmed the safety of daily dosing for these different durations of therapy. [7] Quality-of-life data will be reported in a separate article.

Patients and Methods

Patient Population

This open-label, multicenter study screened patients with a clinical diagnosis of onychomycosis of the toenails in order to enroll at least 1,500 patients with verified disease. [7]

Inclusion Criteria. Patients enrolled in the study had to meet the following criteria [7]:

• Age 18 years or older
• Onychomycosis of the toenails confirmed by either positive potassium hydroxide (KOH) wet mount, positive fungal culture performed at a central laboratory, or both
• Affected toenails capable of regrowth

Exclusion Criteria. Patients were excluded from the study if they met any of the following conditions:

• Had received systemic antifungal therapy within 3 months, topical therapy for the affected nail within 1 month, or any investigational agent within 12 weeks before beginning treatment with terbinafine
• Had psoriasis, mucocutaneous candidiasis, or known immunodeficiencies
• Were pregnant or breast-feeding (pregnancy tests were performed on screening and at the end of treatment, and all females with childbearing potential were advised to practice contraception during the course of the study)
• Had liver disease, nephropathy, or blood disorders that the investigator believed could alter the pharmacokinetic activity of terbinafine
• Had any disease that could significantly impair gastrointestinal absorption of the drug
• Had baseline hepatic enzyme test results greater than 1.5 times the upper limit of normalcy
• Had any abnormal laboratory values that the investigator considered to be clinically significant
• Had a history of alcohol or substance abuse

Treatment

All patients received a single 250-mg tablet of terbinafine once daily. The large toenail was chosen as the target toenail because it takes the longest time to grow out clear. Therefore, this nail would reflect the most difficult-to-treat cases, minimizing bias. The duration of therapy was determined by the extent of onychomycotic involvement of the target toenail at baseline. Patients with less than 50% involvement of the target great toenail and those who had no great-toenail involvement received 12 weeks of therapy. Patients with at least 50% involvement of the target great toenail initially received 12 weeks of therapy. If the assessment at week 12 indicated less than 25% improvement from baseline, the patient received an additional 6 weeks of therapy. This process was repeated at week 18, with patients demonstrating less than 25% improvement from baseline receiving another 6 weeks of therapy. The protocol specified that the maximum duration of therapy was 24 weeks.

Efficacy Evaluation

At the screening visit, one of the two great toenails was designated as the target toenail for assessment of efficacy. If neither great toenail was affected, the target toenail was the one that was most severely affected.

Onychomycosis of the toenails was confirmed by either positive KOH wet mount, positive fungal culture performed at a central laboratory, or both.7

The primary efficacy assessment consisted of mycologic response as indicated by culture and KOH wet mounts performed at all visits. The endpoints of mycologic response were 1) negative mycologic cultures, 2) negative KOH results, and 3) mycologic cure, defined as both negative culture and negative KOH results.

The secondary efficacy assessment consisted of 1) clinical cure, defined as 0% involvement of the target toenail; 2) near clinical cure, defined as greater than 0% but no more than 10% involvement of the target toenail; 3) mycologic and/or clinical recurrence at week 72 in patients who had achieved clinical cure by week 48; and 4) global assessments by physicians and by patients of the therapeutic effect of terbinafine.

Results

Patient Population and Demographics

Of the 2,062 patients from 259 centers screened, 1,548 from 251 centers met the enrollment criteria. The intent-to-treat population consisted of 1,534 patients in whom target toenail involvement was determined in all but one patient. Their baseline demographics are summarized in Table 1. The majority (67.3%) of patients were male, and the mean age of the total population was approximately 50 years. In the majority of patients, onychomycotic infection was extensive and chronic. For example, 81% of the study group exhibited at least 50% involvement of the target toenail, and the mean duration of all infections was more than 11 years.

Table 1. Baseline Demographic and Clinical Characteristics of Intent-to-Treat Population (N = 1,534).

Table 1. Baseline Demographic and Clinical Characteristics of Intent-to-Treat Population (N = 1,534).

Duration of Treatment

As shown in Table 2, comparable numbers of patients completed 12, 18, and 24 weeks of terbinafine therapy. While the protocol specified that patients with less than 50% involvement of the target toenail at baseline were to receive 12 weeks of treatment, 52.2% of these patients actually received more than 12 weeks of therapy. Therapy extended past 25 weeks in 12.6% of patients. In addition, 110 patients received less than 11 weeks of treatment; the reasons were adverse events (67), failure to return for follow-up (17), protocol violation (6), withdrawal of consent (6), and miscellaneous or unknown reasons (14).

Table 2. Baseline Toenail Involvement by Treatment Duration.

Table 2. Baseline Toenail Involvement by Treatment Duration.

As expected, there was a strong positive association between the baseline target toenail involvement (<50% or ≥ 50%) and the duration of treatment (<11, 12, 18, 24, or >25 weeks), as evidenced by Goodman-Kruskal’s γ statistic (γ = 0.298, with an SE of 0.044; P < .001). [8]

In all efficacy analyses, “12 weeks” refers to patients receiving 11 to 13 weeks of treatment; “18 weeks” of therapy covers 14 to 19 weeks of treatment, and “24 weeks” covers a range of 20 to 25 weeks of treatment. Patients completing less than 11 weeks of therapy are not included in any efficacy analysis.

Mycologic Efficacy

The mycologic efficacy of the various treatment durations of terbinafine is shown in Table 3. Because of the various treatment durations of each group, it was deemed inappropriate to perform statistical significance testing.

Table 3. Mycologic Efficacy at End of Study (Week 72) by Treatment Duration.

Table 3. Mycologic Efficacy at End of Study (Week 72) by Treatment Duration.

At the end of the study (week 72), the percentage of patients with negative cultures ranged from 87.5% of patients treated for 12 weeks to 94.4% of patients treated for 24 weeks. The percentage of patients with negative KOH results at week 72 ranged from 73.7% of patients who had received 12 weeks of therapy to 77.7% of those receiving 24 weeks of treatment. Rates of mycologic cure (negative culture plus negative KOH) were also high: 72.1% in the 12-week group, 72.5% in the 18-week group, and 77.0% in the 24-week group. Both patient groups, those with less than 50% and those with 50% or greater toenail in-volvement, were combined for the measurement of mycologic and clinical efficacy.

Clinical Efficacy

The rates of clinical cure for the various treatment groups are summarized in Table 4. In all groups, clinical cure rates were higher at week 72 than at week 48: 49.5% of the 12-week group, 49.2% of the 18-week group, and 44.6% of the 24-week group experienced clinical cure at the end of the study.

Table 4. Clinical Cure Rates at Week 48 and at Week 72 by Treatment Duration.

Table 4. Clinical Cure Rates at Week 48 and at Week 72 by Treatment Duration.

Recurrence

Mycologic recurrence was defined as the occurrence of one positive mycologic result at week 72 in patients demonstrating mycologic cure by week 48. Clinical recurrence was defined as no involvement of the target toenail at week 48, but involvement at week 72. As shown in Table 5, both mycologic and clinical recurrence rates were generally low in all treatment groups, ranging from 14.1% to 17.3%. Patients with less than 50% and those with 50% or greater toenail involvement were combined for the purpose of measuring rates of recurrence.

Table 5. Mycologic and Clinical Recurrence at Week 72 by Treatment Duration.

Table 5. Mycologic and Clinical Recurrence at Week 72 by Treatment Duration.

Global Assessments

Physician Assessment. The percentages of patients considered by physicians to have “clear” or “nearly clear” toenails at week 48 were as follows: 12 weeks, 64.3%; 18 weeks, 63.0%; 24 weeks, 44.5%; and more than 25 weeks, 52.6%. At the end of the study, the majority of patients in all treatment groups received positive assessments from their physicians: 12 weeks, 62.7%; 18 weeks, 58.4%; 24 weeks, 56.9%; and more than 25 weeks, 56.2%.

Patient Assessment. More than 80% of patients in each treatment group rated treatment with terbinafine as either “very good” or “good” at both week 48 and week 72.

Patients also reported that terbinafine treatment improved the quality of their lives. At the end of the study, 68.8% of patients were very satisfied or satisfied with the appearance of their toenails, 76.0% with treatment results, and 76.3% with the most bothersome aspects of the disease, such as pain with walking or inability to feel one’s toes.

Discussion

In this large clinical trial, 250 mg of terbinafine administered once daily for 12, 18, or 24 weeks was highly effective in treating onychomycosis of the toenail—including previously chronic and intractable infections. The extended follow-up period in this study provided an opportunity to assess the efficacy of treatment over longer periods than studied previously. Although there were patients who withdrew from the therapy or otherwise deviated from the protocol, the efficacy results reported here parallel the results seen in other clinical trials.

The study demonstrated that improvement continues well past the 48-week assessment period. Rates of both mycologic and clinical efficacy for all treatment durations continued to increase after the end of treatment, indicating continued activity of terbinafine in the affected nail and regrowth of healthy nail. Because a positive KOH test result does not distinguish between viable and nonviable organisms, a positive KOH result may persist even after an onychomycotic infection has been treated successfully, becoming negative only when the keratin harboring nonviable organisms has been shed.

Since over twothirds of patients were satisfied with how their toenails looked at the end of the study and more than 75% were satisfied with the aspects of the disease that had bothered them most (walking pain, toe numbness, etc), it is clear that effective treatment may help clinicians overcome barriers to a high quality of life.

The efficacy results reported here should be interpreted with caution, since treatment duration was contingent on failure to improve at an earlier time point and this contingency could introduce bias into the results.

Summary

The results of this study confirm the efficacy of terbinafine in the treatment of toenail onychomycosis as demonstrated in previous registration and largescale clinical trials. The majority of patients in all treatment-duration groups achieved mycologic cure by the end of the study; clinical cure rates at the 48-week assessment continued to increase at the final assessment at week 72. The long duration of follow-up allowed a clinically meaningful look at recurrence rates, which were low among all treatment groups.