Introduction

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With a prevalence among adults of 2-4%^1-4 onychomycosis is one of the most common nail diseases and one of the few that are curable, providing it is diagnosed correctly. Systemic treatments for onychomycosis now include terbinafine, an allylamine that is primarily fungicidal, and itraconazole, a triazole that is primarily fungistatic; both represent a major therapeutic advance over griseofulvin in the treatment of this condition. For toenail infections terbinafine is usually taken continuously for 12 weeks, whereas itraconazole is taken either continuously for the same period or intermittentlythat is, 1 week in 4 weeks for 12 or 16 weeks.

Two double blind studies which compared the efficacy of continuous treatment with terbinafine and itraconazole in onychomycosis have both shown terbinafine to be significantly superior. ^{5 6} Because therapeutic concentrations of itraconazole are believed to persist in the nail for a considerable time after systemic treatment is stopped, intermittent therapywith higher daily doses to achieve and maintain therapeutic concentrationsmight be an effective alternative to continuous treatment. Such intermittent treatment is widely used currently to treat onychomycosis and is claimed to be as effective for this indication as both continuous itraconazole and continuous terbinafine. ^{7 8}

Few direct comparisons of continuous terbinafine versus intermittent itraconazole for onychomycosis exist and those that do are relatively small open studies.⁹ We conducted the first large scale, double blind comparison of continuous terbinafine with intermittent itraconazole in the treatment of toenail onychomycosis.

	Methods

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Protocol
Study outline We undertook a prospective, randomised, double blind, double dummy, multicentre, parallel group study over 72 weeks. A total of 38 investigators from 35 centres in six European countries (Finland, Germany, Iceland, Italy, the Netherlands, and the United Kingdom) participated in the study, the objective of which was to compare the efficacy and safety of continuous terbinafine with intermittent itraconazole in the treatment of toenail onychomycosis.

Assignment
Treatment was assigned according to a predetermined computer generated randomisation code produced by Novartis. Thus study treatments (groups T₁₂, T₁₆, I₃, I₄) were randomly allotted to sequential patient numbers in balanced blocks of four by centre and investigators then allocated patient numbers sequentially at baseline.

Blinding
Details of blinding are summarised in table 1. All patients took one tablet a day for weeks 1 to 16, either active (terbinafine 250 mg) or placebo. All patients also took two capsules twice daily (total of four capsules daily), either active (itraconazole 100 mg) or placebo, for weeks 1, 5, 9, and 13. All placebo tablets and capsules were identical in taste and appearance to the respective active compounds. The randomisation code was stored with Novartis and nobody involved in the conduct of the study had access to the code until the database was complete and locked.

	Results

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Participant flow and follow up
A total of 843 patients were screened (figure 1) but 336 of these were excluded because of negative results on fungal culture, withdrawal of consent, protocol violations, or failure to return to the clinic. The 507 remaining patients were randomised for treatment, of whom 506 constituted the study population and 496 the intention to treat population (the 10 patients excluded violated the inclusion or exclusion criteria but had received at least one dose of medication). There were no significant differences at baseline between the four treatment groups with regard to demographics or to the extent and duration of nail disease (table 2).²

View larger version (24K): [in this window] [in a new window]   Fig 1.   Distribution of participants in study, showing randomisation of intention to treat population between four treatment groups and number of patients remaining in each group at weeks 48 and 72. T12 and T16 indicate allocation to terbinafine for 12 or 16 weeks. I3 and I4 indicate allocation to itraconazole for 1 week a month for 3 or 4 months. Patients not randomised (n=336) because of negative results on microscopy or fungal culture, or both, at baseline (n=263); protocol violation (n=19); withdrawal of consent (n=18); or other (n=36). Reasons for the 87 withdrawals (for T12, T16, I3, and I4, respectively) were adverse events (8, 13, 5, 8); withdrawal of consent (2, 1, 3, 2); protocol violation (0, 2, 2, 5); treatment failure (0, 0, 8, 6); failure to return (4, 4, 4, 4); and other (0, 3, 3, 0)

Analysis
Causal agents The species of dermatophyte isolated at screening were Trichophyton rubrum (443; 89.3%), T rubrum plus a non-dermatophyte mould (8; 1.6%), T rubrum plus T mentagrophytes (3; 0.6%), or T mentagrophytes alone (42; 8.5%). Also, of all the patients screened for whom a fungus was cultured, dermatophytes were encountered in 95.7% (555/580).

Cure rates
Table 3 and figure 2 summarise the overall cure rates. Differences in mycological cure significantly favoured terbinafine in all comparisons (P<0.0001), and all comparisons for clinical cure showed significant superiority of both terbinafine regimens versus either of the intermittent itraconazole regimens (P0.0022). As with the mycological cure rates the clinical cure rates for the continuous terbinafine groups continued to increase after treatment through to week 72. This was not the case for the intermittent itraconazole groups. All comparisons also showed significantly higher rates of complete cure in the continuous terbinafine groups compared with both the itraconazole regimens (P0.0044). For clinical effectiveness and global assessments all comparisons showed significantly higher rates of cure for the continuous terbinafine groups (P< 0.0001).

View larger version (20K): [in this window] [in a new window]   Fig 2.   Rates (%) of mycological cure, clinical cure, and complete cure. All comparisons P<0.0001 except for clinical cure T12 v I3 P<0.0015, T12 v I4 P=0.0022; and for complete cure T12 v I3 P=0.0007, and T12 v I4 P=0.0044

Safety
A total of 236 patients reported at least one adverse event (55 for T₁₂, 61 for T₁₆, 60 for I₃, and 60 for I₄). All were within the known safety profile of both drugs, and there were no significant differences in adverse events between the four treatment regimens. The most commonly reported adverse events were nausea, headache, upper respiratory tract infection, chest infection, back pain, flu-like symptoms, bronchitis, and fever, although most were considered by the investigators to be mild or moderate and unrelated to the study medications.

	Discussion

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We have shown in this study that terbinafine 250 mg a day over 12 or 16 weeks produces better mycological and clinical cure rates at week 72 than intermittent itraconazole given over the same periods. Rates of clinical cure for terbinafine improved clearly and consistently until the 72 week end point, whereas for itraconazole there was no significant improvement beyond week 48. Both drugs were well tolerated, with the adverse events reported or observed within the established tolerability profile of each drug.¹⁰ The causal fungi seen in this study were the same as noted in previous studies, ^{11 12} with dermatophytes accounting for the infection in 96% of the 580 participants screened for whom a fungus was cultured and, by definition, in all 496 patients randomised to treatment.

One possible explanation for the superior efficacy of terbinafine in this study is provided by the reported differences in fungistatic and fungicidal concentrations of the two drugs. Terbinafine has a primary fungicidal action against dermatophyte fungi with mean minimum inhibitory (MIC) and minimum fungicidal (MFC) concentrations of around 0.004 µg/ml, while itraconazole is primarily fungistatic, with mean MFC of about 0.6 µg/ml in dermatophytes.¹³ Terbinafine concentrations found in the nail are thus around 100-fold higher than the MFC of the drug,¹⁴ while the reported concentrations of itraconazole are on the borderline between fungistatic and fungicidal action.¹⁵ If fungicidal action is indeed important for effective clearing of onychomycosis variation in itraconazole concentrations in different patients might influence the therapeutic outcome, while in the case of terbinafine elimination of the pathogen would be achieved despite a wide range of variation. This therapeutic advantage is probably more evident in this study as the participants generally had severe onychomycosis, reflected by a relatively high percentage involvement of the target toenail (mean 70.4%), longstanding disease (mean 10.6 years), and, on average, onychomycosis in five other toenails.

	Acknowledgments

The principal investigators of the LION study were J P Steinsson, B Sigurgeirsson, J H Olafsson (Iceland); R Suhonen, T Rantanen, S Stubb, H Heikkilä (Finland); K Gründer, J Ring, M Goos, E G Jung, E Haneke, G Niedergesäss, E Schöpf, P Altmeyer, T Ruzicka, D Reinel (Germany); R E Boelen, L Hamminga, H J van der Rhee, T M Starink, D J Tazelaar, B J Vermeer, J Wuite, D de Hoop, L P Montnor (Netherlands); P Biggio, E di Fonzo (Italy); M J D Goodfield, D T Roberts, J Berth-Jones, D Haworth, I U Haque, C Langdon, V Mittal, R Williams, R Cranfield, R Baldwin (United Kingdom).

Contributors: EGVE assisted with the planning of the study, was responsible for all the mycological investigations, helped with the interpretation of the results, and was principally responsible for writing and revising the paper. BS was the principal study investigator and as such assisted with the planning of the study and was responsible for the final content of the protocol. BS also made a major contribution to the clinical work of the study, helped with the interpretation of the results, and assisted with writing and revising the paper. Both authors are guarantors.

	Footnotes

Funding: Novartis Pharmaceuticals Corporation.

Conflict of interest: EGVE has received funds for research and attending symposia and also fees for speaking and consulting from a number of pharmaceutical companies, including Novartis Pharma and Janssen Pharmaceuticals. BS has received funds for research and fees for speaking and organising educational meetings from several pharmaceutical companies, including Novartis Pharma. Novartis manufactures Lamisil (terbinafine).

	References

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(Accepted 10 February 1999)