Original article

A comparative clinical study between 2 weeks of luliconazole 1%

cream treatment and 4 weeks of bifonazole 1% cream treatment
for tinea pedis

Shinichi Watanabe,1 Hisashi Takahashi,1 Takeji Nishikawa,2 Iwao Takiuchi,3 Nobuhiko Higashi,4
Katsutaro Nishimoto,5 Saburo Kagawa,6 Hideyo Yamaguchi7 and Hideoki Ogawa8
1
Department of Dermatology, Teikyo University School of Medicine, Itabashi, 2Department of Dermatology, Keio University School of Medicine, Shinjuku,
Tokyo, 3Department of Dermatology, Showa University Fujigaoka Hospital, Aoba, Yokohama, 4Department of Dermatology, Municipal Sakai Hospital, Sakai,
Osaka, 5Department of Dermatology, Nagasaki Municipal Hospital, Shinchi-machi, Nagasaki, 6Department of Dermatology, Showa University School of
Medicine Higashi Hospital, Nishi nakanobu, Shinagawa, Tokyo, 7Teikyo University, Institute of Medical Mycology, Otsuka, Hachioji, Tokyo, and 8Department
of Dermatology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan

Summary The aim of the study was to compare the efficacy and safety of luliconazole 1% cream
and bifonazole 1% cream as applied in the treatment of tinea pedis (interdigital-type
and plantar-type). A multi-clinic, randomised single-blind, parallel group study with
34 hospitals and 11 clinics formed the study design. Five hundred and eleven patients
with mycologically confirmed tinea pedis were included. Of the 489 evaluable patients,
247 were randomised to luliconazole, and 242 to bifonazole. Luliconazole 1% cream
applied once a day for 2 weeks, followed by a placebo cream for 2 weeks, thereafter.
Bifonazole 1% cream applied once a day for 4 weeks. Mycological effect (negative result
on microscopy) and improvement of skin lesions were measured at weeks 1, 2, 3 and 4.
Safety frequency and severity of adverse reactions were also measured. The
improvement of skin lesions after 4 weeks was comparably good with rates of 91.5%
vs. 91.7% (luliconazole vs. bifonazole). The mycological effect was characterised by
high negative rates of 76.1% vs. 75.9% (luliconazole vs. bifonazole). The progression of
tinea-related signs and symptom scores differed insignificantly between evaluated
luliconazole and bifonazole treatment groups comprising a total of 500 patients. Both
substances appeared to be comparably safe and well-tolerated.

Key words: new antimycotic, luliconazole, phase III comparative clinical study.

Introduction
Although many excellent topical antifungal agents
for tinea and candidiasis have been recently devel-
oped,1,2,3,4 the number of sufferers has not decreased.5
Therefore, in the area of clinical practice, an antifungal
agent with stronger antifungal and fungi-eradicating
activity, as well as good retention in the skin is in high
demand.6
Correspondence: Shinichi Watanabe, Department of Dermatology, Teikyo
University School of Medicine, 11-1, Kaga-2, Itabashi, Tokyo 173-8605,
Japan. Tel.: +81 3 3964 2469. Fax: +81 3 5375 5314.
E-mail: watanabe@med.teikyo-u.ac.jp
Accepted for publication 30 November 2005
Luliconazole(PR-2699,NND-502),((-)-(R)-(E)-[4-(2,4-
dichlorophenyl)-1,3-dithiolan 2-ylidene]-l-imidazolylac-
etonitrile) is a novel imidazole antifungal drug synthe-
sised by Nihon Nohyaku Co., Ltd,7 which exhibits a
broad spectrum of activity against dermatophytes,
yeasts and dimorphic fungi. A summary of the lulicon-
azole studies is as follows.
In the non-clinical study, application of luliconazole
1% cream for 2 days indicated superior effectiveness,
which corresponded to that after application of lanoc-
onazole 1% cream, terbinafine 1% cream, or bifonazole
1% cream for 4 days.7 The topical treatment with
luliconazole also resulted in a mycological cure in a
guinea pig model in which plantar skin samples were
fungus free even at 16 weeks (20 weeks postinfection)

2006 The Authors

236 Journal Compilation
2006 Blackwell Publishing Ltd • Mycoses, 49, 236–241

after completion of the treatment (no fungal re-growth
was observed).8
The skin irritation indexes in the luliconazole phase-I
clinical study were within the range specified for a safe
product. The test drug was well-tolerated by subjects in
the single- and repeated-application studies.
In the early phase-II clinical study considering the
treatment period of luliconazole, the efficacy for tinea
pedis at Week 4 was nearly the same for the conven-
tional treatment group (4 week-treatment) and the
shortened treatment group (2 week-treatment). Adverse
reactions were mild/insignificant and no additional
treatment was required.
In the late phase-II clinical study considering appro-
priate dosage, three groups – luliconazole 1%, 0.5% and
0.1% cream groups – were employed for the shortened
treatment to determined the optimal dosage of lulicon-
azole, and the efficacy and safety of luliconazole were
investigated amongst the three groups by the random-
ised double-blind comparative method (note: 2 week-
treatment). The efficacy rates in improvement of skin
lesions (evaluated at week 4) for each group were very
high at above 90%. The mycological effect (evaluated at
week 4) was characterised by high rates and the
eradication rate tended to increase concentration-
dependently. From these results, it was concluded that
the optimal dosage form of the test cream is 1%. In the
phase-III clinical study, a single-blind comparative
study was designed to compare the efficacy and safety
of luliconazole 1% cream to those of the control drug
bifonazole9,10 in patients with tinea pedis.
Patients and methods
A multi-clinic, randomised, single-blind, parallel two-
group comparison study including 511 patients
between the ages of 20 and 74 years, from 45 hospitals
was performed. All patients had presented clinically
(a) Week 0 Week 1
Group A (luliconazole 1% cream) ‘1st Drug’ (active drug)
Group B (bifonazole 1% cream) ‘1st Drug’ (active drug)
(b)
(i) Time frame of improvement of skin symptoms, mycological effect and safety
(ii) Fungi culture
: Evaluation point
Figure 1 Endpoints and timing of evaluation.

2006 The Authors
Journal Compilation
2006 Blackwell Publishing Ltd • Mycoses, 49, 236–241
Single-blind comparative study
with mycologically confirmed tinea pedis. Informed
consent was obtained from all patients before the start
of treatment. Excluded from this trial were pregnant
women; patients with contact dermatitis or secondarily
infected lesions in the affected area; those with severe
hyperkeratosis on the sole; those with an extremely
wide area of eroded skin; those currently taking
systemic steroid medication; those treated with systemic
antimycotics within 8 weeks, or with topical antimy-
cotics within 4 weeks; those with a serious illness (e.g.
diabetes mellitus, collagen diseases, auto-immune dis-
eases, haematological diseases and malignant tumours);
and, those with serious liver disfunction, kidney
disfunction or cardiac problems.
Patients were assigned to receive treatment with
luliconazole cream 1%, or with bifonazole cream 1%
according to a block randomisation method for each
interdigital type and plantar type. These medications
were supplied in tubes that were identical in appear-
ance. Subjects were enrolled and randomised to receive
luliconazole 1% cream once daily for 2 weeks, followed
by a placebo cream for 2 weeks. Subjects randomised to
receive bifonazole cream 1% received this cream for
4 weeks (see Fig. 1).
Luliconazole cream was supplied by Pola Chemical
Industry Co., Ltd, Yokohama, Japan, and bifonazole 1%
cream was kindly supplied by Bayer Yakuhin Co.,
Osaka, Japan. Both creams were supplied in identical
unmarked tubes.
At the start of treatment and at each follow-up visit,
signs and symptoms such as itching, erythema, pus-
tules/vesicles, maceration, erosion and scaling were
scored as follows: absent (0), mild (1), moderate (2),
severe (3), aggravated from severe (4; except at the
start). Direct examinations of the lesions under study
were performed by the KOH method at each visit. The
total of scores for each cutaneous symptom was
compared with that at the start of the trial to evaluate
Week 2 Week 3 Week 4
‘2nd drug’ (placebo)
‘2nd drug’ ( active drug)
237
S. Watanabe et al.
the rate of improvement of cutaneous symptoms as
gauged according to the following ratings of improve-
ment of skin lesions: significantly improved (0% to 25%
remaining), moderately improved (between 25% and
50% remaining), mildly improved (between 50% and
75% remaining), basically unchanged (between 75%
and 100% remaining), and aggravated (100% or more
remaining). Based on the mycological effects and the
improvement of skin lesions rates, the overall clinical
effects were also evaluated. Mycological testing (culture
study) was performed for KOH-positive patients at the
2-weeks visit. Probable adverse events and tolerability
were recorded at each visit. Blood tests (haematology
and blood chemistry) and urine testing were performed
at each visit. Statistical analyses at each visit included
the following: Fisher’s Exact Test, or the Conhran–
Mantel–Haenszel Statistic for Qualitative Variables, and
Student’s t-test, or Wilcoxon’s Rank Sum Test for
Quantitative Variables. The Generalised Wilcoxon Test
was used to determine the statistical significance of the
time frame of improvement of skin symptoms, and the
time frame of mycological effects (microscopic exam-
ination).
Results
Patients
A total of 511 patients with tinea pedis were entered
into the clinical trial. As shown in Table 1, the patient
characteristics of the two groups of evaluable patients
(247-luliconazole vs. 242-bifonazole) were well-
matched. The spectrum of identified fungal species at
the initial visit was elucidated. The severity of the
current episode of tinea pedis was similar in the two
groups, as indicated by the total indications and
symptoms scores. At baseline, 305 of the 489 patients
had a culture-confirmed dermatophyte infection. The
species of the responsible fungi were: Trichophyton
Table 1 Patient characteristics.
Luliconazole Bifonazole
Patients 247 242
Age (average) 20–74 (48.6) 20–74 (49.4)
Gender
Male 147 (59.5%) 137 (56.6%)
Female 100 (40.5%) 105 (43.4%)
Tinea pedis
Interdigital 119 (48%) 123 (51%)
Plantar 128 (52%) 119 (49%)
Weight (kg) 62.9 ± 11.2 62.5 ± 11.3
Height (cm) 162.7 ± 8.6 162.2 ± 9.3
238
rubrum [43% (61/151) in the luliconazole group, 38%
(58/154) in the bifonazole group, Trichophyton mentagr-
ophytes [50% (75/151) in luliconazole, 43% (66/154)
in bifonazole], E. floccosum [0% in luliconazole, 1% (2/
154) in bifonazole], and Trichophyton spp. [7% (11/151)
in luliconazole, 18% (28/154) in bifonazole].
Clinical efficacy
The efficacy rate for the improvement of skin lesions
(patients exhibiting Ômoderate improvementÕ or better/
patients eligible for evaluation), at 4 weeks after treat-
ment was comparable at 91.5% vs. 91.7% (luliconazole
vs. bifonazole) for the full analysis set (P ¼ 1.000;
Table 2, left). Based on the efficacy rate for the improve-
ment of skin symptoms at Weeks 1, 2, 3 and 4, the time
frame of improvement of skin symptoms effect was
analysed. A nearly equal kinetics of skin improvement
ratio was observed for the two groups (P ¼ 0.5102,
generalised Wilcoxon test, Fig. not shown).
Mycological efficacy
KOH study
Mycological effect was evaluated as negative in 76.1%
vs. 75.9% (luliconazole vs. bifonazole; Table 2, right). A
nearly equal time frame for improvement of mycological
examination was observed among the two treatment
groups (P ¼ 0.8294, generalised Wilcoxon test, Fig. not
shown). No discrepancy was identified for the two
evaluation items in the results, and a non-recessive
characteristic favouring the bifonazole or luliconazole
was verified.
Culture study
Because 135 of 247 luliconazole-treated patients and
125 of 242 bifonazole-treated patients had negative
KOH results at the end of 2 weeks of treatment, other
positive patientsÕ skin specimens (luliconazole:112, bif-
onazole 115) were cultured to determine the presence of
alive fungi. As shown in Table 3, right), 73% of patients
in the luliconazole group were culture negative even if
they had microscopically positive specimens. In con-
trast, only 50% of patients in the bifonazole group were
culture negative.
Safety evaluation
The progression of scores of tinea-related indications
and symptoms revealed no relevant differences between
the luliconazole and bifonazole treatment groups
(Table 4).

2006 The Authors
Journal Compilation
2006 Blackwell Publishing Ltd • Mycoses, 49, 236–241
 Single-blind comparative study

Table 2 Efficacy 1: clinical and mycological (KOH) comparison of the two treatment groups (FAS).

Clinical Mycological (KOH)

Variable Luliconazaole Bifonazole Luliconazaole Bifonazole

Cure (patients) 91.5 (226/247) 91.7 (222/242) 76.1 (188/247) 75.9 (183/241)
P-value 1 1

The primary response criterion defined as independent improvement of skin lesions (clinical) and mycological response.

Table 3 Efficacy 2: Overall and mycological (culture) comparison of the two treatment groups (FAS).

Overall [clinical + mycologocal (KOH)] Mycological (culture)

Variable Luliconazaole Bifonazole Luliconazaole Bifonazole

Cure (patients) 74.1 (183/247) 73.4 (177/241) 73.2 (82/112) 49.6 (57/115)
P-value 0.918 0.0004

Overall clinical effects at week 4.

Mycological (culture) was evaluated in KOH positive patients (LCZ: 112, BFZ: 117) in week 2.

Table 4 Appearance of drug related adverse events in the two symptoms disappear, although no mycological cure
treatment groups. Safty analysis, n ¼ 500. may have yet been achieved. In such cases, dermato-
phytes are not completely eradicated from the infected
Luliconazaole Bifonazole
Adverse event (n ¼ 253) (n ¼ 243) sites and consequently a recurrence may occur. There-
fore, superior antimycotic action achievable through
Itching 2 3 short-term therapy has been desired for tinea pedis
Erythema 0 1
Skin-inflammation 0 1
patients.6
Hotness 1 0 Although the standard treatment period for the
Irritation 2 2 clinical trial of antifungal agents has long been 4 weeks
Pain 1 0 for tinea pedis in Japan,10 based on the results of non-
Redness 1 1 clinical studies such as short-term therapy using an
Total no. of events 7 8
Total no. of patients (%) 5/253 (2.0%) 6/247 (2.4%)
animal model, and results from early phase II/late phase
II clinical studies, the possibility of shortening the
treatment period for luliconazole 1% cream was indica-
ted and the treatment period for luliconazole cream was
Discussion
set at 2 weeks for tinea pedis.
In the previous dose-finding study of luliconazole, the
adopted evaluation procedures were a modification of
Primary endpoint in terms of efficacy
the antimycotic clinical trial prescribed in Japan,10, 11
and used in the phase III clinical trial. With respect to the main evaluation of luliconazole, two
items, namely the degree of improvement of skin lesions
and the mycological effect (microscopic examination),
Modifications of the treatment regime for the clinical
were elucidated independently in this study. By compar-
trial
ing two groups, a luliconazole group (half the treatment
Although many excellent topical antifungal agents have period of bifonazole) and a bifonazole group (standard/
been developed,12,13,14 the number of patients with original treatment period), the efficacy and safety rates for
tinea pedis has not decreased. One reason that no luliconazole in the short-treatment period group were
significant improvement has been observed in topical found to be nearly the same as those for the bifonazole
antifungal therapy may be poor compliance with when evaluations were performed at week 4. In addition,
treatments. In particular, because it is difficult for most no discrepancy was found in the two evaluation items
patients to continue regular topical application for a regarding results, and a non-recessive characteristic
long period, most usually stop treatment after clinical favouring bifonazole or luliconazole was verified.

2006 The Authors

Journal Compilation
2006 Blackwell Publishing Ltd • Mycoses, 49, 236–241 239
S. Watanabe et al.
Mycological assessment by culture study
Previously, the superiority or inferiority of the study
medicine could not be accurately judged by KOH
examination because of the presence of both living
and dead fungi in the specimens of KOH preparation.
However, in this clinical trial, because of the adminis-
tration of the culture study of the skin at 2 weeks after
beginning application, significant differences in the
presence of living fungi were observed in the skin
specimens from patients in the two clinical groups.
Thus, the superiority of luliconazole treatment over
bifonazole was observed (Table 3, P ¼ 0.0004, Fisher).
Culture studies proved that luliconazole eradicated
fungi in the skin through short-term treatment, even
when the presence of fungal elements was confirmed
under the microscope. Luliconazole 1% cream exhibited
superior efficacy through application for a period of only
2 weeks. Superior results of short-term treatment with
luliconazole 1% cream were proven.
Acknowledgments
We thank our colleagues for their contributions to this
study, and for allowing us to use their data: Juntendo
University School of Medicine (Hiruma H.), Keio Uni-
versity School of Med. (Nishikawa T.), Showa University
School of Med. Fujigaoka Hospital (I. Takiuchi), Showa
University School of Med. Higashi Hospital (Iijima M.),
Juntendo University School of Med, Juntendo-Urayasu
Hospital (Takamori K.), Tokyo Women’s Medical Col-
lege, Daini Hospital (Harada T.), Nihon University
School of Med. Nerima-Hikarigaoka Hospital (Yamagu-
chi Z.), Kitasato University School of Med. (Katsuoka
N.), Toshiba Hospital (Matumoto T.), Kanto Chuo
Hospital (Hino H.), Kosei Hospital (Shimozuma M.),
Nakano Sogo Hospital (Maruyama R.), Tokyo Police
Hospital (Iozumi K.), Asahikawa Medical College (Asano
K.), Saiseikai-Kawaguchi Hospital (Kato T.), Tokyo
Koseinennkin Hospital (Nankoh H.), Kohtoh Hospital
(Iwahara K.), Shimizu City Hospital (Sugiura M.),
Yokohama City University School of Med. (Ikezawa
Z.), Yokohama City University School of Med. Sogo-Iryo-
Center (Sasaki T.), Yokohama Municipal Hospital
(Mohri S.), Japanese Red Cross Yokohama Hospital
(Takahashi Y.), International Goodwill Hospital
(Yamada Y.), Kanazawa Medical Univ. (Ishizaki H.),
Gifu University Scholl of Medicine (Kitajima Y.), Gifu
Prefectural Hospital (Maeda M.), Ohgaki Municipal
Hospital (Seishima M.), Sakai Municipal Hospital (Higa-
shi N.), Yamaguchi University School of Med. (Muto
M.), Nagasaki Municipal Hospital (Nishimoto K.),
240
Kyusyu University Faculty of Medical Science, School
of, Med. (Furue M.), University of Occupational and
Environmental Health, Japan (Asahi S.), Tohoku
Koseinenkin Hospital (Kato T.), Kyusyu Koseinenkin
Hospital (Murakami Y.), Kasai Clinic (Kasai T.), Saitoh
Clinic (Saito S.), Makino Clinic (Makino Y.), Kusunoki
Clinic (Kusunoki T.), Naka Clinic (Naka I), Taneda
Clinic (Taneda A.), Imai Clinic (Imai R.), Matsuda Clinic
(Matsuda T.), Matsuda Tomoko Clinic (Matsuda T.),
Kiryu Clinic (Kiryu H.), Yamano Clinic (Yamano T.).
References
1 Stettendorf S. Tolerability and efficacy of bifonazole in
dermatomycoses. Arzneim Forsch/Drug Res 1983; 33:
750–4.
2 Petranyi G, Ryder NS, Stitz A. Allylamine derivatives; new
class of synthetic antifungal agents inhibiting fungal
squalene epoxidase. Science 1984; 224: 1239–41.
3 Arika T, Yokoo M, Hase T, Maeda T, Amemia K, Yamaguti
H. Effects of butenafine hydrochloride. A new benzylamine
derivative, on experimental dermatophytosis in guinea
pig. Antimicrob Agents Chemother 1990; 34: 2250–3.
4 Ohmi T, Konaka S, Uchida M, Yamaguchi H. Antifungal
activity of the new agent lanoconazole in two tinea
models. Arzneim Forsch/Drug Res 1991; 41: 847–51.
5 Epidemiological Investigation Committee for Human
Mycoses in the Japanese Society for Medical Mycology
(Co-chairman and reporter:Kasai T.). 1997 Epidemiologi-
cal survey of dermatophytoses in Japan. Jpn J Med Mycol
2001; 42: 11–8.
6 Watanabe S. Present state and future direction of topical
antifungals. Jpn J Med Mycol 1999; 40: 151–5.
7 Niwano Y, Kuzuhara N, Kodama H, Yoshida M, Miyazaki
T, Yamaguchi H. In vitro and in vivo antidermatophyte
activities of NND-502, a novel optically active imizazole
antimycotic agent. Antimicrob Agents Chemothr 1998; 42:
967–70.
8 Uchida K, Tanaka T, Yamaguchi H. Achievement of
complete mycological cure by topical antifungal agent
NND-502 in guinea pig model of tinea pedis. Micobiol
Immunol 2003; 47: 143–6.
9 Wagner W, Reckers-Czaschka R. Oxiconazole in derma-
tomysosis – a double-blind, randomized therapy study to
compare with bifonazole. Mycoses 1987; 30: 484–92.
10 Kagawa S, Takahashi S, Takahashi H, Nishikawa T,
Watanabe S. SS717 Clinical Research Group. Clinical
evaluation of SS717 cream in the treatment of dermato-
mycosis – a randomized comparative study with bifonaz-
ole cream as a control. Clin Rep 1991; 25: 415–46.
11 Kagawa S, Clinical efficacy of terbinafine in 629 Japanese
patients with dermatomycosis. Clin Exp Dermatol 1989;
14: 114–5.
12 Smith EB, Graham JL, Ulrich JA, Topical clotrimazole in
tinea pedis. South Med J 1977; 70: 47–8.

2006 The Authors
Journal Compilation
2006 Blackwell Publishing Ltd • Mycoses, 49, 236–241

13 Lackner TE, Clissold SP. Bifonazole; a review of its anti-
microbial activity and therapeutic use in superficial myc-
oses. Drugs 1989; 38: 204–25.
14 Suschka S, Fladung B, Merk HF. Clinical comparison of
the efficacy and tolerability of once-daily Canestin with

2006 The Authors
Journal Compilation
2006 Blackwell Publishing Ltd • Mycoses, 49, 236–241
Single-blind comparative study
twice-daily Nisoral (clotrimazole 1% cream vs. ketocon-
azole 2% cream) during a 28-day topical treatment of
interdigital tinea pedis. Mycoses 2002; 45: 91–6.
241