Terbinafine

Evans EG, Sigurgeirsson B. Double-blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. BMJ 1999; 318:1031-5.

Clinical question How do continuous terbinafine and intermittent itraconazole compare in efficacy and safety for the treatment of toenail onychomycosis?

Background Onychomycosis is one of the most common nail diseases, and one of the few that is treatable. Commonly used systemic therapies include terbinafine, which is primarily fungicidal, and itraconazole, which is primarily fungistatic. Because itraconazole persists in therapeutic concentrations after discontinuation of treatment, it is commonly prescribed in a pulse-like manner. This study is the first large-scale double-blind comparison of continuous terbinafine and intermittent itraconazole.

Population studied The study included men and women aged 18 to 75 years from 35 centers in 6 European countries with the clinical diagnosis of onychomycosis. All had involvement of the great toe confirmed by a positive mycologic culture and positive KOH microscopy. Patients were excluded for use of systemic antifungals in the previous 12 months or topical antifungals in the previous 4 weeks, and for drugs or conditions known to interact with the effectiveness or safety of the study drugs.

Study design and validity This was a prospective randomized double-blind

multicenter parallel group study lasting 72 weeks that was funded by Novartis, the manufacturer of terbinafine. Patients were randomly allocated to 1 of 4 groups: [T.sub.12], terbinafine 250 mg (1 tablet) once a day for 12 weeks; [T.sub.16], terbinafine 250 mg (1 tablet) once a day for 16 weeks; [I.sub.3], itraconazole 400 mg (4 capsules) each day for 1 week in every 4 weeks for a 12-week period; and [I.sub.4], itraconazole 400 mg (4 capsules) each day for 1 week in every 4 weeks for a 16-week period. Placebo tablets and capsules were used "double dummy" to ensure that all patients took 1 tablet a day for 16 weeks plus 4 capsules a day during the 1st, 5th, 9th, and 13th weeks. The 4 groups were similar regarding mean age, percentage of women, race, number of infected toenails, species of dermatophyte causing infection, proportion of target nail involved, and duration of current episode of infection. Compliance criteria were appropriate and well defined. Results were analyzed on an intention-to-treat basis.

The lack of a control group was a primary limitation, and the reported results contained minimal statistical data. Incomplete explanation was provided for discrepancies between the number of patients used in the tabulation of the final results and the number of patients who completed the study. And treatment other than experimental medication was not delineated. For example, did patients file nails, receive any other confounding medications once the study began, or change hygiene habits? Finally, the evaluation of drug safety did not describe the methods used to collect complaints of side effects and lacked laboratory data to further support safety, such as follow-up monitoring of the initially gathered liver function tests and creatinine levels.

Outcomes measured The primary disease-oriented outcome was mycologic cure at 72 weeks, defined as negative culture and KOH microscopy. The primary patient-oriented outcomes were clinical cure (100% toenail clearing) at 72 weeks, complete cure (mycologic and clinical cure), and clinical effectiveness (mycologic cure and at least 5 nun of new clear toenail growth). Patients and physicians made global assessments of the perceived condition of all affected at weeks 12 and 72; the amount of improvement was rated on a scale from poor to excellent.

Results Of the 496 patients randomized to 1 of 4 treatment groups, 409 completed the study. The authors accounted for all withdrawals. Mycologic cure rates were: [T.sub.12] = 76% (81 of 107); [T.sub.16] = 81% (80 of 99); [I.sub.3] = 38% (41 of 107); and 14 = 49% (53 of 108); P [is less than] .001. In all other outcomes measured, terbinafine was also shown to be significantly superior (range = P [is less than] .001 to P [is less than or equal to] .004). However, the clinical cure rate was much lower than the mycologic cure rate in all treatment groups: [T.sub.12], 54% (59 of 110); [T.sub.16], 60% (59 of 98); [I.sub.3], 32% (34 of 107); and [I.sub.4], 32% (35 of 109). Therefore, the percentage of complete cure, a combination of both mycologic and clinical cure, was also lower: [T.sub.12], 46% (49 of 107); [T.sub.16], 55% (54 of 98); [I.sub.3], 23% (25 of 107); and [I.sub.4], 26% (28 of 108). Only 6.8% (34 of 496) withdrew for adverse events, and those patients were evenly distributed among the 4 groups.

Recommendations for clinical practice Continuous terbinafine is more effective than intermittent itraconazole at achieving the goal of clear toenail growth. There was 1 additional clinical cure at 72 weeks for every 4.3 patients treated for 12 weeks with continuous terbinafine. However, there are additional important considerations for the physician when determining whether to initiate any medical therapy for toenail onychomycosis. These include the low rate of complete cure, a significant rate of patient withdrawal because of adverse events, the high cost of treatment, any concurrent patient conditions (human immunodeficiency virus or acquired immunodeficiency syndrome, diabetes, immunocompromise, and so forth), and a recurrence rate of at least 22%[1] at 3 years after successful initial treatment.

REFERENCE

[1.] Tosti A, Piraccini BM, Stinchi C, Colombo MD. Relapses of onychomycosis after successful treatment with systemic antifungals: a three-year follow-up. Dermatology 1998; 197:162-6.

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