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British Journal of Dermatology 1999; 141 (Suppl. 56): 5±14. L.I.ON. Study: ef®cacy and tolerability of continuous terbina®ne (LamisilÒ) compared to intermittent itraconazole in the treatment of toenail onychomycosis B.SIGURGEIRSSON, S.BILLSTEIN*, T.RANTANEN², T.RUZICKA³, E.DI FONZO§, B.J.VERMEER¶, M.J.D.GOODFIELD** AND E.G.V.EVANS²², FOR THE L.I.ON. STUDY GROUP Reykjavik City Hospital, Department of Dermatology, Hudlaeknastodin ehf, Smartorg 1, 200 Kopavogur, Iceland E-mail: [email protected] *Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA ²Paijat-Hame Central Hospital, Lahti, Finland ³Department of Dermatology, University of DuÈsseldorf, Germany §Istituto di Clinica Dermosi®lopatica, UniversitaÁ di Firenze, Italy ¶Leiden University Medical Center, Leiden, The Netherlands **General In®rmary, Leeds, UK ²²Public Health Laboratory Service (PHLS) Mycology Reference Laboratory, University of Leeds and General In®rmary, Leeds, UK Summary We undertook a prospective, randomised, double-blind, double-dummy, multicentre, parallel-group study to compare the ef®cacy and tolerability of continuous terbina®ne (LamisilÒ) with intermittent itraconazole (SporanoxÒ) in the treatment of toenail onychomycosis. A total of 496 patients (age range 18±75 years) with a clinical diagnosis of dermatophyte toenail onychomycosis, con®rmed by positive mycological culture and microscopy (KOH), were recruited from 35 centres in six European countries. They were randomly divided into four parallel groups to receive either terbina®ne 250 mg/ day for 12 or 16 weeks (groups T12 and T16), or itraconazole 400 mg/day for 1 week in every 4 weeks for 12 or 16 weeks (groups I3 and I4). The primary ef®cacy measurement at week 72 was mycological cure, de®ned as negative microscopy and negative culture of samples from the target toenail. At week 72, the mycological cure rates were 75´5% (81/107) in the T12 group and 80´8% (80/99) in the T16 group, compared with 38´3% (41/107) in the I3 group and 49´1% (53/108) in the I4 group. All comparisons (T12 vs. I3, T12 vs. I4, T16 vs. I3, T16 vs. I4) showed signi®cantly higher cure rates in the terbina®ne groups (all P < 0´0001). In addition, all secondary clinical outcome measures were signi®cantly in favour of terbina®ne at week 72. Both treatments were well tolerated, with no signi®cant differences in the number or type of adverse events reported. We conclude that continuous terbina®ne is signi®cantly more effective than intermittent itraconazole in the treatment of toenail dermatophyte onychomycosis. Onychomycosis (fungal infection of the nails) is a common disease. Two studies conducted by questionnaire in the UK1 and Spain2 found a prevalence of around 3% in the adult population, with a prevalence approaching 5% in older adults.1 More recently, a mycology-based study from Finland3 and a study from Iceland (B. Sigurgeirsson, personal communication) have suggested an overall prevalence of 8%. The prevalence of onychomycosis is even higher in special Investigators in the LamisilÒ vs. Itraconazole in Onychomycosis (L.I.ON.) Study Group are listed at the end of the article. q 1999 British Association of Dermatologists populations, such as patients with diabetes mellitus, psoriasis, and the elderly: recently, a prevalence of 30% has been demonstrated in regular swimmers.4,5 Bearing in mind the potentially serious physical, psychosocial, and occupational effects of the disease,6 it is no surprise that most sufferers are willing to consider drug therapy to cure their condition.7 In the great majority of cases, onychomycosis can now be cured, using one or other of the available systemic treatments. These include terbina®ne (LamisilÒ), an allylamine with primarily fungicidal properties, and itraconazole (SporanoxÒ), a triazole 5 6 B.SIGURGEIRSSON et al. that is primarily fungistatic. Both agents offer therapeutic advantages over griseofulvin, which was for many years the mainstay of treatment for onychomycosis.8 For toenail onychomycosis, terbina®ne is usually prescribed daily for 12 weeks, whereas itraconazole is either prescribed in the same manner or intermittently for 1 week every 4 weeks for 12 or 16 weeks. Two double-blind comparative studies in toenail onychomycosis9,10 have shown that continuous terbina®ne 250 mg/day for 12 weeks achieves statistically superior rates of mycological cure (at 48 and 52 weeks, respectively) than itraconazole 200 mg/day over the same period. A smaller study11 has also shown a trend towards greater ef®cacy for continuous terbina®ne compared to intermittent itraconazole, but others12 have claimed that intermittent itraconazole is equally effective. The present study is the ®rst to compare continuous terbina®ne with intermittent itraconazole in the treatment of toenail onychomycosis on a suf®ciently large scale to enable statistically signi®cant conclusions to be reached. We have opted to call this study the L.I.ON. study (Lamisil vs. Itraconazole in ONychomycosis), and the primary study report has recently been published in the BMJ.13 Subjects and Methods We undertook a prospective, randomised, multicentre, double-blind, double-dummy, parallel-group study to compare the ef®cacy and tolerability of continuous terbina®ne with intermittent itraconazole in the treatment of toenail onychomycosis. Patients were recruited from 35 centres in six European countries: Finland, Germany, Iceland, Italy, the Netherlands, and the UK. They were randomly allocated to one of four treatment groups: terbina®ne 250 mg/day for 12 weeks (group T12) or 16 weeks (group T16), or itraconazole 400 mg/ day for 1 week every 4 weeks for either 12 weeks (group I3) or 16 weeks (group I4). A double-dummy system was used to blind the study treatment: patients received either active terbina®ne tablets and placebo capsules, or active itraconazole capsules and placebo tablets. In order to ensure absorption of itraconazole, patients were instructed to take all study medication with meals. A total of 843 patients were initially screened for inclusion, but 336 were eliminated for various reasons ± negative microscopy and/or negative fungal culture (263), withdrawal of consent (18), protocol violation (19), or other reasons (36). Thus 507 patients were randomised to treatment, of whom 506 constituted the tolerability population and 496 the intent-to-treat (ITT) population used for assessment of ef®cacy (n 124 in group T12, n 120 in group T16, n 126 in group I3 and n 126 in I4). The study ¯ow chart is shown in Fig. 1. All patients started treatment within 6 weeks of screening, and were evaluated every 4 weeks during the treatment phase (i.e. week 0±16) and then at weeks 24, 36, 48 and 72 (end of study). Both investigators and Figure 1. The study ¯ow chart for the intention-to-treat population (n 496). Patients entered the study within 6 weeks of screening. q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14 L.I.ON. STUDY Organism(s) Number of cultures Acremonium sp. Acremonium sp. Trichophyton rubrum Aspergillus niger Aspergillus sp. Candida guilliermondi Candida parasilosis Cladosporum sp. Fusarium sp. Fusarium sp. Trichophyton rubrum Scopulariopsis brevicaulis Scopulariopsis brevicaulis Trichophyton rubrum Scopulariopsis sp. Trichophyton mentagrophytes Trichophyton mentagrophytes Trichophyton rubrum Trichophyton rubrum Total positive cultures 7 Table 1. Distribution of cultures in patients at screening. Of 843 patients, 580 yielded positive culture results 1 3 1 2 1 2 1 3 2 13 5 1 46 4 495 580 patients remained blinded throughout the entire 72week study. The tolerability population was de®ned as all patients randomised to treatment who received at least one dose of study medication; the ITT population was de®ned as above, and in addition satis®ed all inclusion and exclusion criteria. Patients were regarded as non-compliant if they failed to take more than two complete daily doses of study medication in any one week or more than seven doses in any one month: such patients were discontinued from the study. Inclusion and exclusion criteria Patients eligible for inclusion were men and women aged between 18 and 75 years with a clinical diagnosis of distal subungual or total dystrophic onychomycosis of Table 2. Baseline demographics of the intent-to-treat population (n 496). There are no statistically signi®cant differences between the four treatment groups with respect to any parameter. SD Standard Deviation Parameter All patients Number Mean age 6 SD 496 50´1 6 12´8 Group T12 124 50´1 6 12´3 Group T16 120 50´9 6 13´1 Group I3 126 50´7 6 12´6 Group I4 126 48´6 6 13´1 Gender % Male % Female 58´1 41´9 57´3 42´7 56´7 43´3 57´1 42´9 61´1 38´9 Race % Caucasian % Other 98´6 1´4 97´6 2´4 99´2 0´8 99´2 0´8 98´4 1´6 89´3 8´5 0´6 91´9 6´5 0´0 85´8 11´7 0´0 88´9 9´5 0´0 90´5 6´3 2´4 1´6 1´6 2´5 1´6 0´8 5´8 6 2´9 5´6 6 2´8 6´0 6 2´8 5´6 6 2´8 5´9 6 2´9 70´4 6 26´6 73´7 6 25´5 69´9 6 25´3 69´7 6 26´2 68´5 6 29´0 10´6 6 9´5 11´8 6 10´3 10´5 6 9´7 10´4 6 8´8 9´9 6 9´3 Dermatophytes (%) T. rubrum T. mentagrophytes Both the above T. rubrum plus non-dermatophyte mould Infected nails (n) Mean 6 SD Nail involvement Mean percentage 6 SD Duration of current episode Mean years 6 SD q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14 8 B.SIGURGEIRSSON et al. Figure 2. Rates of mycological cure (%) at various stages throughout the study. At week 72, all comparisons were signi®cantly in favour of the terbina®ne groups, P < 0´0001. Figure 3. Global assessment of ef®cacy of terbina®ne by (a) patients and (b) physicians. At week 72, all comparisons were signi®cantly in favour of the terbina®ne groups, P < 0´0001. q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14 L.I.ON. STUDY the toenails con®rmed by positive mycological culture and microscopy (KOH examination). Only patients with dermatophyte infections were included, and all were required to have involvement of a great toenail (designated the target nail) capable of regrowth. Involvement of the great toenail is generally agreed to indicate cases that are more dif®cult to treat. All mycological examinations were performed centrally at the Public Health Laboratory Service Mycology Reference Laboratory, Leeds, UK. Exclusion criteria were typical for a study of this type. Those excluded comprised pregnant and lactating women; women of child-bearing age not using adequate contraception; persons receiving drugs known or believed to interact with either of the study agents; and persons with conditions that might lead to altered absorption, metabolism or excretion of the study agents. Other exclusion criteria were systemic antifungal therapy within the 12 months prior to the screening visit, or topical antifungal therapy within the 4 weeks prior to the screening visit; diagnosis of immunode®ciency disorder, psoriasis or mucocutaneous candidiasis; radiotherapy, chemotherapy or immunosuppressive therapy within 12 weeks of the start of the study; and alanine transaminase and/or aspartate transaminase levels more than 1´5 times the upper limit of the normal range and/or serum creatinine level above 300 mmol/L. The study protocol conformed to `Good Clinical Practice for Trials on Medicinal Products in the European Community'; the US Code of Federal Regulations dealing with clinical studies; and the Declaration of Helsinki on medical research in humans. All patients gave written, informed consent, witnessed independently. In addition, the study protocol was subject to Institutional Review Board approval at each study centre. 9 Figure 4. Clinical ef®cacy at week 72 (% of patients in each treatment group). All comparisons were signi®cantly in favour of the terbina®ne groups, P < 0´0001. good (considerable improvement); fair (slight improvement) or poor (no change or worse). In addition, investigators calculated the percentage nail improvement from baseline by dividing the nail into quadrants. This allowed subsequent calculation of the percentage area of clear growth (to the nearest 10%) at baseline and at intervals throughout the study. Statistical analysis The study achieved its objective of randomising at least 120 patients to each treatment group. Based on the assumption of a 70% mycological cure rate with itraconazole, the study had 80% power to detect a 15% difference at the 5% level of signi®cance. Discrete variables ± mycological and clinical cure, clinical ef®cacy, and global assessments ± were analysed by the Ef®cacy criteria The primary criterion of ef®cacy was mycological cure, de®ned as negative microscopy (KOH) and negative fungal culture of samples taken from the target toenail (great toenail) at week 72. Secondary ef®cacy criteria were clinical cure (100% toenail clearing at week 72), complete cure (mycological and clinical cure), clinical ef®cacy (mycological cure and at least 5 mm of new clear toenail growth from baseline) and global assessments of ef®cacy undertaken by both patient and physician. These were made at each visit from week 12 to the end of the study, based on the perceived condition of all affected nails, and using a 4-point rating scale: very good or excellent (minimal or no signs and symptoms); Figure 5. Rates of clinical cure (%) at various stages throughout the study. At week 72, all comparisons were signi®cantly in favour of the terbina®ne groups: T12 vs. I3, P < 0´0015; T12 vs. I4, P 0´002; T16 vs. I3 and T16 vs. I4, P < 0´0001. q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14 10 B.SIGURGEIRSSON et al. Figure 6. Rates of complete cure (%) at various stages throughout the study. At week 72, all comparisons were signi®cantly in favour of the terbina®ne groups: T12 vs. I3, P 0´0007; T12 vs. I4, P 0´004; T16 vs. I3 and T16 vs. I4, P < 0´0001. Cochran±Mantel±Haenszel statistical test, adjusting for country. Continuous variables ± area of involvement and length of new clear toenail growth ± were analysed using analysis of variance (ANOVA), with treatment, country, and treatment by country as terms in the model. (a) Results Toenail samples were taken from all patients initially screened (n 843), of which 580 (68´8%) were positive for a fungus (Table 1). Dermatophytes were present in 555 (95´7%) of the positive cultures and non-dermatophytes (b) Figure 7. Toenail appearance of: (a) a member of T12 at study start (top panel), week 16 (middle), and week 72 (bottom); and (b) a member of I3 at study start (top), week 16 (middle), and week 72 (bottom). Photographs reproduced with the kind permission of Dr Tapio Rantanen, Paijat-Hame Central Hospital, Lahti, Finland. q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14 L.I.ON. STUDY in the remaining 25 (4´3%); in 10 patients dermatophytes and non-dermatophytes coexisted. The dominant species was Trichophyton rubrum, which occurred as sole causative agent in 89´3% of ITT patients (n 443), and in combination with T. mentagrophytes or a non-dermatophyte in 2´2% (n 11): T. mentagrophytes was the sole causative agent in 8´5% of ITT patients (n 42). A total of 288 men (58´1%) and 208 women (41´9%) were randomised to treatment. The mean age of the patients was 50´1 years (range 18±76). In total, 430 (98´6%) randomised patients were Caucasian. Patients of Asian or Oriental race comprised the remainder. There were no signi®cant differences between the four treatment groups with respect to the basic demographics given above, as well as severity and duration of nail disease, prior therapy or causative pathogen. The mean number of infected toenails was 5´8, with mean involvement of the target nail being 70% and mean disease duration 10´6 years. These data are summarised in Table 2. Assessment of ef®cacy Ef®cacy results are based on the number of observed cases in the ITT population at 72 weeks. Analyses were also performed using the `last observation carried forward' method. Results did not change statistically using this method, nor were there any statistical differences in results when the two populations were separately analysed. Mean compliance was more than 99% in all treatment groups. Mycological cure At week 72, mycological cure rates (Fig. 2) were 75´7% (81/107) for T12, 80´8% (80/99) for T16, 38´3% (41/ 107) for I3, and 49´1% (53/108) for I4. All comparisons (T12 vs. I3, T12 vs. I4, T16 vs. I3, and T16 vs. I4) were statistically in favour of the terbina®ne regimens, P < 0´0001 in all cases. Global assessment and clinical ef®cacy At week 72, global assessment of ef®cacy by patients (Fig. 3a) was rated very good or excellent in 78´9% (T12), 78´8% (T16), 43´9% (I3), and 52´3% (I4). Physicians (Fig. 3b) rated global ef®cacy as very good or excellent in 79´1% (T12), 84´8% (T16), 52´3% (I3), and 55´1% (I4). All comparisons were statistically in favour of the terbina®ne regimens, P < 0´0001 in every case. 11 Both the patients and the physicians remained blinded for these assessments. At week 72, the clinical ef®cacy (de®ned as mycological cure and at least 5 mm of new clear toenail growth from baseline) was 65´7% (67/102) for T12, 70´5% (67/ 95) for T16, 28´4% (29/102) for I3, and 33´7% (35/ 104) for I4. All comparisons at week 72 were again statistically in favour of the terbina®ne regimens, P < 0´0001 (Fig. 4). Clinical cure and complete cure At week 72, clinical cure (de®ned as 100% toenail clearing at 72 weeks) was 53´6% (59/110) for T12, 60´2% (59/98) for T16, 31´8% (34/107) for I3, and 32´1% (35/109) for I4. All comparisons were again statistically in favour of the terbina®ne regimens (Fig. 5). As with mycological cure (Fig. 2), clinical cure rates in the terbina®ne groups continued to increase through to 72 weeks, whereas rates in the itraconazole groups tended to level out after 36 weeks. Complete cure requires both negative microscopy and culture and 100% toenail clearing. At week 72, complete cure rates were 45´8% (49/107) for T12, 55´1% (54/98) for T16, 23´4% (25/107) for I3, and 25´9% (28/ 108) for I4. All comparisons were statistically in favour of the terbina®ne regimens (Fig. 6). Complete cure rates for terbina®ne continued to increase through to 72 weeks, whereas those for itraconazole tended to level out. In Figure 7, the appearance of the target toenail of a member of T12 at study start, week 16 and week 72 is compared with that of a member of I3. Percentage nail involvement By week 72, the mean percentage change (improvement) from baseline was 58´3% in T12, 54´7% in T16, 30´1% in I3, and 35´1% in I4. All comparisons were statistically in favour of terbina®ne, P < 0´0001. Safety Both agents were well tolerated, with no statistically signi®cant differences in the number and type of adverse events between the four treatment groups. A total of 444 adverse events were reported by 236 patients: n 55 in T12, n 61 in T16, n 60 in I3, and n 60 in I4. Of these, 140 were considered de®nitely, probably or possibly related to the study medications: n 37 in T12, n 38 in T16, n 35 in I3, and n 30 in I4 (Table 3). All adverse events reported or observed were within the established tolerability pro®les for both study medications.Table 3 q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14 12 B.SIGURGEIRSSON et al. Table 3. Adverse events de®nitely, probably, or possibly related to study medication, divided by treatment group Parameter Headache Skin disturbance Visual disorders Taste disturbance Thrombophlebitis Red cell disorders Hepatic and biliary events Gastrointestinal disturbances Other events Discussion Recent studies have shown that the prevalence of onychomycosis is as high as 8% in the general population, and even higher in selected groups. In a population based study in Iceland, over 90% of patients with suspected onychomycosis wanted treatment, given that an effective treatment exists (B. Sigurgeirsson, personal communication). Despite this, studies1,2 have shown that almost 50% of infected patients have never taken medical advice about their condition, and that few of those seeking advice are prescribed systemic therapy. Now that effective treatment for onychomycosis exists, physicians have increasingly realised that onychomycosis is more than a cosmetic problem. The condition is often symptomatic, causing discomfort and sometimes pain. Cosmetic and functional disability can also be signi®cant and can adversely affect quality of life. The absence of spontaneous remission means that infection will not resolve of its own accord and often spreads to the soles, causing ®ssuring and pain. It will prove dif®cult to eradicate dermatophytes from communal bathing places until a concerted effort is made to reduce the number of infected individuals using these facilities. Terbina®ne is a member of the allylamine class of synthetic antimycotic agents. It is thus both chemically and mechanistically distinct from other oral antifungal agents.14 In vitro, terbina®ne is active against a broad spectrum of fungi ± dermatophytes, moulds and yeasts ± with very low minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) levels against most pathogens.14 Terbina®ne exhibits primarily fungicidal activity against dermatophytes,15,16 as evidenced by the close similarity of its MIC and MFC levels against various fungi. By contrast, triazoles such as itraconazole have a primarily Group T12 (n 55) Group T16 (n 61) Group I3 (n 60) Group I4 (n 60) 0 2 0 2 1 0 1 15 16 7 2 0 3 0 1 0 17 8 4 2 0 2 0 0 0 20 7 3 2 1 1 0 0 3 10 10 fungistatic action against dermatophytes. In vitro, terbina®ne is up to 200 times more potent than griseofulvin, and approximately 20 times more potent than itraconazole, against dermatophyte species.16 In vivo, high concentrations of terbina®ne, ®ve times the MIC level for dermatophytes, are found in both the proximal and distal regions of the nail within a few weeks of commencing oral therapy.17 This therapeutic advantage of terbina®ne is likely to be more evident in this study where the patients generally had dif®cult-to-treat onychomycosis, with long duration of disease (mean 10´6 years), high percentage involvement of the target toenail (mean 70´4%), and onychomycosis in an average of ®ve other toenails. Two previous studies9,10 have compared continuous terbina®ne with continuous itraconazole, while a third11 has compared continuous terbina®ne with intermittent itraconazole. In the ®rst,9 the ef®cacy of terbina®ne 250 mg/day was compared to itraconazole 200 mg/day in patients with toenail onychomycosis. Treatment duration was 12 weeks, with follow-up until 48 weeks after commencement of the study. At week 48, mycological cure rates (de®ned as negative microscopy and culture) were 73% in the terbina®ne group (n 163), compared to only 45´8% in the itraconazole group (n 168), P < 0´0001. A similar study,10 again in patients with toenail onychomycosis, compared the ef®cacy of terbina®ne 250 mg/day for 12 weeks (n 86) with itraconazole 200 mg/day for 12 weeks (n 84). At follow-up, 52 weeks after commencement of treatment, rates of mycological cure (as de®ned above) were 81% in the terbina®ne group, compared to only 63% in the itraconazole group, P < 0´01. Itraconazole is now more usually prescribed as an intermittent therapy, typically 400 mg/day for seven days every 28 days for 12 or 16 weeks. This regimen has been claimed to be as effective as continuous q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14 L.I.ON. STUDY terbina®ne for the treatment of onychomycosis.12 To date, few direct comparisons have been made in this context, and the relevant studies are small. However, an open, randomised study11 has compared the ef®cacy of continuous terbina®ne 250 mg/day for 16 weeks with intermittent terbina®ne 500 mg/day and intermittent itraconazole 400 mg/day, prescribed for 7 days every 28 days for 16 weeks. Patients (n 21 in each group) had mycologically con®rmed dermatophyte toenail onychomycosis. At 6 months after completion of therapy, mycological cure rates were 94´1%, 80´0% and 75´5%, respectively. Complete cure (mycological cure plus 100% toenail clearing) was seen in 78´9% of patients in the continuous terbina®ne group, compared to only 38´0% in the intermittent itraconazole group. The L.I.ON. study is the ®rst to compare the ef®cacy and tolerability of continuous terbina®ne with intermittent itraconazole in a suf®ciently large group of patients to provide statistically signi®cant conclusions. We have shown that terbina®ne 250 mg/day for 12 or 16 weeks is statistically superior to intermittent itraconazole 400 mg/day given for 1 week every 4 weeks for 12 or 16 weeks in the treatment of patients with toenail onychomycosis. This is the case whatever criteria are used ± mycological cure, clinical cure, clinical ef®cacy, complete cure or global assessment of ef®cacy by patient or physician. Terbina®ne achieves high rates of mycological and clinical cure at week 48, and maintains or even improves these rates at week 72 (Figs 2, 5 and 6): by contrast, mycological and clinical cure rates for itraconazole peak at week 48 and either level off or fall thereafter. The causal fungi found in this study were the same as noted in previous studies,8,9 with dermatophytes accounting for the infection in almost 96% of the 580 culture-positive screened patients (Table 1). Both agents were well tolerated, with adverse events within the known tolerability pro®les of each drug.18 Unlike triazoles, terbina®ne acts by inhibiting the enzyme squalene epoxidase, a non-cytochrome P-450 enzyme. This mode of action suggests that terbina®ne is unlikely to exhibit signi®cant drug±drug or drug± disease interactions. This belief has been con®rmed by the results of a postmarketing surveillance study in 25,884 patients in a primary care setting.4,19,20 At week 72, both terbina®ne regimens were statistically superior to both itraconazole regimens in terms of mycological cure (the primary criterion of ef®cacy), and in terms of clinical cure, clinical ef®cacy, complete cure and patient and physician global assessments (secondary criteria of ef®cacy), in the treatment of onychomycosis. Terbina®ne may thus be considered 13 the drug of choice for the treatment of toenail onychomycosis. Chairman's overview Randomised, double-blind, placebo-controlled studies such as this one now provide persuasive evidence that terbina®ne is the treatment of choice in patients with onychomycosis. Terbina®ne achieves mycological and clinical cure more rapidly than itraconazole, and is signi®cantly superior to itraconazole, as measured by these (and other) parameters, at 48, 52, and 72 weeks after commencement of the relevant study (see also the presentations of Dr Roberts and Dr De Cuyper for more details of these studies). The simple dosing regimen (one 250 mg tablet daily) and short duration of treatment (6 weeks for ®ngernail and 12 weeks for toenail disease) aid compliance. Acknowledgements The L.I.ON. Study investigators would like to thank Farid Kianifard (study statistician) and Angela Verzilli (study scientist) of Novartis Pharmaceuticals Corporation; ICON Clinical Research (Dublin, Ireland), who administered the Study and produced the ®nal Study Report; the staff of the PHLS Mycology Reference Laboratory (Leeds, UK), who undertook the mycological investigations, and Mikko Sinisalo and Tony Williams of Novartis Pharma AG, Basel, Switzerland. L.I.ON. study principal investigators: Finland, R.Suhonen, T.Rantanen, S.Stubb, H.HeikkilaÈ; Germany, K.GruÈnder, J.Ring, M.Goos, E.G.Jung, E.Haneke, G.NiedergesaÈss, E.SchoÈpf, P.Altmeyer, T.Ruzicka, D.Reinel; Iceland, J.P.Steinsson, B.Sigurgeirsson, J.H.Olafsson; Italy, P.Biggio, E.di Fonzo; Netherlands, 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; United Kingdom, M.Good®eld, D.T.Roberts, J.BerthJones, D.Haworth, I.U.Haque, C.Langdon, V.Mittal, R.Williams, R.Cran®eld, R.Baldwin. Con¯ict of interest: Dr Sigurgeirsson has received funds for research and fees for speaking and organising educational meetings from several pharmaceutical companies, including Novartis Pharma. Professor Evans has received funds for research and also fees for speaking and consulting from a number of pharmaceutical companies, including Novartis Pharma and Janssen Pharmaceuticals. 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