Download efficacy and tolerability of continuous terbinafine (Lamisil®)

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 ˆ 124 in
group T12, n ˆ 120 in group T16, n ˆ 126 in group I3
and n ˆ 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 ˆ 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 ˆ 496). There are no statistically signi®cant differences between the four
treatment groups with respect to any parameter. SD ˆ 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 ˆ 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 ˆ 0´0007; T12 vs. I4, P ˆ 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 ˆ 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 ˆ 443), and in combination with T. mentagrophytes
or a non-dermatophyte in 2´2% (n ˆ 11): T. mentagrophytes was the sole causative agent in 8´5% of ITT
patients (n ˆ 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 ˆ 55 in
T12, n ˆ 61 in T16, n ˆ 60 in I3, and n ˆ 60 in I4. Of these,
140 were considered de®nitely, probably or possibly
related to the study medications: n ˆ 37 in T12, n ˆ 38
in T16, n ˆ 35 in I3, and n ˆ 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 ˆ 55)
Group T16
(n ˆ 61)
Group I3
(n ˆ 60)
Group I4
(n ˆ 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 ˆ 163), compared to only 45´8% in the itraconazole group (n ˆ 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 ˆ 86) with itraconazole 200 mg/day for
12 weeks (n ˆ 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 ˆ 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. Dr Billstein is an employee of
Novartis Pharmaceuticals Corporation, USA.
q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14
14
B.SIGURGEIRSSON et al.
References
1 Roberts DT. Prevalence of dermatophyte onychomycosis in the
United Kingdom: results of an omnibus survey. Br J Dermatol
1992; 126 (Suppl. 39): 23±7.
2 Sais G, JugglaÁ A, PeryõÂ J. Prevalence of dermatophyte onychomycosis in Spain: a cross-sectional study. Br J Dermatol 1995; 132:
758±61.
3 HeikkilaÈ H, Stubb S. The prevalence of onychomycosis in Finland.
Br J Dermatol 1995; 133: 699±703.
4 Gupta AK, Lynde CW, Jain HC, Sibbald RG, Elewski BE, Daniel CR
3rd et al. A higher prevalence of onychomycosis in psoriatics
compared with non-psoriatics: a multicentre study. Br J Dermatol
1997; 136: 786±9.
5 Gudnadottir G, Hilmarsdottir I, Sigurgeirsson B. Onychomycosis
in Icelandic swimmers. Acta Derm Venerol (Stockh) 1999; 79:
376±7.
6 Scher RK. Onychomycosis is more than a cosmetic problem. Br J
Dermatol 1994; 130 (Suppl. 43): 15.
7 Lubeck DP. Quality of life in persons with onychomycosis. Qual Life
Res 1993; 2: 341±8.
8 Chiritescu MM, Chiritescu M-E, Scher RK et al. Newer systemic
antifungal drugs for the treatment of onychomycosis. Clin Podiatr
Med Surg 1996; 13: 741±58.
9 De Backer M, De Keyser P, De Vroey C, Lesaffre E. A 12-week
treatment for dermatophyte toe onychomycosis: terbina®ne
250mg/day vs. itraconazole 200mg/day ± a double-blind comparative trial. Br J Dermatol 1996; 134 (Suppl. 46): 16±7.
10 BraÈutigam M, Nolting S, Schopf RE et al. Randomised double blind
11
12
13
14
15
16
17
18
19
20
comparison of terbina®ne and itraconazole for treatment of toenail tinea infection. Br Med J 1995; 311: 919±22.
Tosti A, Piraccini BM, Stinchi C et al. Treatment of dermatophyte
nail infections: an open randomized study comparing intermittent
terbina®ne therapy with continuous terbina®ne treatment and intermittent itraconazole therapy. J Am Acad Dermatol 1996; 34: 595±600.
Gupta AK, Scher RK. Oral antifungal agents for onychomycosis.
Lancet 1998; 351: 541±2.
Evans EGV, Sigurgeirsson B. for the L.I.ON. study group. Double
blind, randomised study comparing continuous terbina®ne with
intermittent itraconazole in the treatment of toenail onychomycosis. Br Med J 1999; 318: 1031±5.
Ryder NS, Favre B. Antifungal activity and mechanism of action of
terbina®ne. Rev Contemp Pharmacother 1997; 8: 275±87.
Hazen K. Fungicidal versus fungistatic activity of terbina®ne and
itraconazole: an in vitro comparison. J Am Acad Dermatol 1998; 38:
S37±S41.
Clayton YM. In vitro activity of terbina®ne. Clin Exp Dermatol
1989; 14: 101±3.
Finlay AY, Lever L, Thomas R, Dykes PJ. Nail matrix kinetics of oral
terbina®ne in onychomycosis and normal nails. J Dermatol Treat
1990; 1 (Suppl. 2): 51±3.
Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview.
Part II. J Am Acad Dermatol 1994; 30: 911±33.
Hall M, Monka C, Krupp P, O'Sullivan C. Safety of oral terbina®ne.
Results of a postmarketing surveillance study in 25, 884 patients.
Arch Dermatol 1997; 133: 1213±1219.
Suhonen R, Neuvonen PJ. The tolerability pro®le of terbina®ne.
Rev Contemp Pharmacother 1997; 8: 373±386.
q 1999 British Association of Dermatologists, British Journal of Dermatology, 141 (Suppl. 56): 5±14