Efinaconazole 10% solution in the treatment of toenail

onychomycosis: Two phase III multicenter,

randomized, double-blind studies
Boni E. Elewski, MD,a Phoebe Rich, MD,b Richard Pollak, DPM,c David M. Pariser, MD,d
Shinichi Watanabe, MD,e Hisato Senda, DVM,f Chikara Ieda, PharB,g Kathleen Smith, MBA,h
Radhakrishnan Pillai, PhD,h Tage Ramakrishna, MD,i and Jason T. Olin, PhDi
Birmingham, Alabama; Portland, Oregon; San Antonio, Texas; Norfolk, Virginia; Tokyo and Kyoto, Japan;
Petaluma, California; and Bridgewater, New Jersey

Background: Onychomycosis is a common nail infection, often resulting in nail plate damage and
deformity. Topical lacquer treatments have negligible efficacy. Oral treatments, although more efficacious,
are limited by drug interactions and potential hepatotoxicity.
Objective: We investigated the safety and efficacy of efinaconazole 10% solution (efinaconazole), the first
triazole antifungal developed for distal lateral subungual onychomycosis.
Methods: Two identical, multicenter, randomized, double-blind, vehicle-controlled studies were con-
ducted in patients with toenail distal lateral subungual onychomycosis (20%-50% clinical involvement
[study 1: N = 870, study 2: N = 785]). Patients were randomized (3:1) to efinaconazole or vehicle, once daily
for 48 weeks, with 4-week posttreatment follow-up. Debridement was not performed. The primary end
point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium
hydroxide examination and fungal culture) at week 52.

Results: Mycologic cure rates were significantly greater with efinaconazole (study 1: 55.2%, study 2: 53.4%)
compared with vehicle (P \.001). The primary end point, complete cure, was also significantly greater for
efinaconazole (study 1: 17.8% vs 3.3%, study 2: 15.2% vs 5.5%, P \ .001). Treatment success (percent
affected target toenail [0%- # 10%]) for efinaconazole ranged from 21.3% to 44.8% in study 1 and from
17.9% to 40.2% in study 2, compared with 5.6% to 16.8% and 7.0% to 15.4%, respectively, with vehicle.
Adverse events associated with efinaconazole were local site reactions (2%) and clinically similar to vehicle.

Limitations: A period of 52 weeks may be too brief to evaluate a clinical cure in onychomycosis.

Conclusions: Once daily topical efinaconazole appears to be a viable alternative to oral treatment options
for onychomycosis. ( J Am Acad Dermatol 2013;68:600-8.)

From the Department of Dermatology, University of Alabama at
Birmingham School of Medicinea; Northwest Cutaneous Re-
search Specialists, Portlandb; San Antonio Podiatry Associatesc;
Department of Dermatology, Eastern Virginia Medical Schoold;
Department of Dermatology, Teikyo University School of Med-
icine, Tokyoe; Kaken Pharmaceutical Co Ltd, Kyotof and Tokyog;
Dow Pharmaceutical Sciences Inc, (a division of Valeant Phar-
maceuticals North America LLC) Petalumah; and Valeant Phar-
maceuticals North America LLC, Bridgewater.i
Supported by Valeant Pharmaceuticals North America LLC, Bridge-
water, NJ. Editorial assistance was provided by Brian Bulley,
MSc, of Inergy Limited, whose fees were paid by Valeant
Pharmaceuticals North America LLC.
Disclosure: Dr Elewski was an advisor to Valeant Dermatology, a
subsidiary of Valeant Pharmaceuticals North America LLC. Dr
Watanabe was a consultant to Kaken Pharmaceuticals Co Ltd,
Hisamitsu Pharmaceutical Co Inc, and Sato Pharmaceutical Co
Ltd. Dr Rich was an investigator with Anacor, Celtic Pharma,
Cipher Pharmaceuticals, Nitric Bio Inc, and Promius Pharma LLC,
and an advisor for Valeant Dermatology, a subsidiary of Valeant
Pharmaceuticals North America LLC. Dr Pariser was a consultant
to Valeant Dermatology, a subsidiary of Valeant Pharmaceuticals
North America LLC, Abbott Laboratories, Amgen, Astellas
Pharma US Inc, Celgene Corp, DUSA Pharmaceuticals, Galderma
Laboratories LP, and Genetech Inc, and an investigator for
Abbott Laboratories, Amgen, Basliea, Celgene Corp, Lilly and
Company, Galderma Laboratories LP, Graceway Pharmaceuticals
LLC, and Intendis Inc. Dr Pollak was an advisor to Valeant
Dermatology, a subsidiary of Valeant Pharmaceuticals North
America LLC. Drs Elewski, Watanabe, Rich, Pariser, and Pollak
were all investigators in the efinaconazole studies. Dr Senda and
Mr Ieda are employees and stockholders in Kaken Pharmaceu-
ticals Co Ltd. Drs Ramakrishna, Pillai, Olin, and Ms Smith are
employees and stockholders in Valeant Pharmaceuticals North
America LLC.
Accepted for publication October 8, 2012.
Reprint requests: Boni E. Elewski, MD, Department of
Dermatology, University of Alabama at Birmingham School of
Medicine, EFH 414, 1530 3rd Ave S, Birmingham, AL
35294-0009. E-mail: beelewski@aol.com.
Published online November 22, 2012.
0190-9622/$36.00
Ó 2012 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2012.10.013

600
J AM ACAD DERMATOL Elewski et al 601
VOLUME 68, NUMBER 4

Key words: efficacy; efinaconazole; onychomycosis; randomized controlled trials; safety; topical triazole
antifungal.

Distal lateral subungual growth, positive potassium

onychomycosis (DLSO) is a CAPSULE SUMMARY hydroxide microscopy result,
common and progressive and culture of dermatophyte
fungal infection of the nail d Onychomycosis is a common nail or mixed dermatophyte/
bed, which may extend into infection that is difficult to treat and Candida less than or equal
the matrix or plate, leading to manage long term. Oral antifungals are to 42 days before baseline.
destruction and deformity of limited by safety concerns and drug Women of childbearing age
toenails and, less frequently, interactions, and topical antifungals by were required to use birth
fingernails.1,2 Prevalence in- modest efficacy. control.
creases with age3-5 and it is d Efinaconazole 10% solution is an Exclusion criteria included:
associated with patient dis- effective treatment for mild to moderate history of immunosuppres-
tress, disability, and pain.6-10 onychomycosis. sion and/or clinical signs
Onychomycosis is challeng- d For patients who would prefer an indicative of possible immu-
ing to treat because of slow efficacious topical onychomycosis nosuppression, known HIV
nail growth and difficulties treatment, efinaconazole provides a infection, uncontrolled diabe-
delivering treatment to the realistic option. tes mellitus, presence of
infection site.3,11 toenail infection other than
Phase III studies of oral dermatophytes, severe mocca-
itraconazole and terbinafine sin tinea pedis at screening/
report complete cure rates of 14% and 38% and baseline, any disease/condition that might have caused
mycologic cure rates of 54% and 70%, respec- toenail abnormalities or interfered with the evaluation,
tively.12,13 Subsequent studies report lower complete and previous target toenail surgery. Patients were not
cure rates.14-17 Oral treatment is limited by drug excluded for concomitant drugs that inhibit cyto-
interactions and risk of acute liver injury (requiring chrome P450 3A4.
laboratory monitoring), which is relevant to elderly Enrolled patients were randomized to receive
patients.18,19 efinaconazole or vehicle (3:1 ratio) self-applied
Patients may prefer an efficacious topical treat- once daily for 48 weeks without debridement, fol-
ment if there are minimal systemic side effects and no lowed by a treatment-free 4-week follow-up.
laboratory monitoring. However, ciclopirox lacquer Treatment was applied to the clean, dry nail plate
has a complete cure rate of 5.5% to 8.5%,12 and surface, lateral and proximal nailfolds, hyponychium,
mycologic cure rates of 34%.20 It requires frequent and undersurface of the nail plate. Patients were
nail debridement and residual lacquer removal.21 assessed for efficacy and safety at baseline, 12-week
Thus, we investigated the safety and efficacy of intervals postbaseline (ie, weeks 12, 24, 36, and 48),
efinaconazole 10% (wt/wt) solution (IDP-108), the and final visit (week 52).
first triazole antifungal developed specifically for the
topical treatment of DLSO.
Randomization and masking
Study drugs were provided in a kit containing
METHODS identical masked bottles with a randomization num-
Study design ber determined by a computer-generated randomi-
In 2 identical, multicenter, randomized, parallel- zation schedule. Access to the randomization
group, double-blind, vehicle-controlled studies, pa- schedule was permitted after both the database
tients with mild to moderate toenail DLSO (defined was locked and the study unblinded. The investiga-
as 20%-50% clinical involvement of the target toenail, tors, sponsor, investigational center staff, clinical
without dermatophytomas or matrix [lunula] involve- monitors, patients, and all other study personnel
ment) were randomized to receive efinaconazole were unaware of study drug assignment to individual
10% solution or vehicle. Eligibility criteria included: patients. In case of a medical emergency where it
18 to 70 years of age, clinical diagnosis of DLSO became necessary to know treatment assignment,
affecting at least 1 great toenail, target toenail unin- the identity was made available to the investigator. If
fected length 3 mm or more (from the proximal the treatment code was broken, the patient was
nailfold), thickness 3 mm or less, evidence of toenail discontinued.
602 Elewski et al
Fig 1. Schematic profile of study disposition.
Study assessment
The primary efficacy end point was the propor-
tion of patients achieving complete cure at week 52
(4-week posttreatment visit) defined as 0% clinical
involvement of the target toenail and mycologic cure
(negative potassium hydroxide examination, and
negative fungal culture of the target toenail sample).
Secondary end points were: mycologic cure, treat-
ment success (\10% clinical involvement of the
target toenail), complete or almost complete cure
(# 5% clinical involvement and mycologic cure), and
unaffected toenail growth (change from baseline).
All secondary end points were assessed at week 52.
Supportive efficacy end points included treatment
success (0%-# 10% clinical involvement of the target
toenail), change in the number of affected nontarget
toenails, change in quality of life, and target toenail
growth. A study investigator assessed the outcomes
at each visit.
Safety assessments included monitoring and
recording of adverse events (AEs) until week 52.
Study oversight
The studies were conducted in accordance with
the ethical principles specified in the Declaration of
Helsinki and in compliance with requirements of
local regulatory committees. All patients provided
written informed consent.
Statistical analysis
Data from each trial were analyzed separately
using software (SAS, SAS Institute Inc, Cary, NC). The
J AM ACAD DERMATOL
APRIL 2013
intent-to-treat population included all patients
randomized and dispensed study drug. The safety
population included all patients who received at least
1 dose of study drug, and 1 postbaseline assessment.
Efficacy end points were compared using
Cochran-Mantel-Haenszel tests (stratified by analysis
center) at a 5% significance level. Unaffected new
toenail growth was analyzed using a 2-way variance
analysis. Missing efficacy data were imputed using
the last observation carried forward method; no
imputations for missing safety data were performed.
All AEs were recorded and classified using the
Medical Dictionary for Regulatory Activities
(MedDRA version 12.1). A Fisher exact test was
used to compare the incidences of treatment-
emergent AEs and treatment-related AEs occurring
with frequencies 1% or higher.
RESULTS
Patients
There were 1655 patients with DLSO randomized
(study 1: 870, study 2: 785) at 118 sites: United States
(study 1: 34, study 2: 36), Canada (study 1: 7, study 2: 8),
and Japan (study 1: 33). Studies were conducted from
December 2009 to September 2011 (study 1: DPSI-IDP-
108-P3-01) and October 2011 (study 2: DPSI-IDP-108-
P3-02) (ClinicalTrials.gov numbers NCT01008033
and NCT01007708). Patients were randomized to
efinaconazole 10% solution (study 1: 656, study 2:
583) or vehicle (study 1: 214, study 2: 202) (Fig 1).
At baseline, patient mean age was 52.3 and 50.6
years (studies 1 and 2, respectively). Patients were
J AM ACAD DERMATOL Elewski et al 603
VOLUME 68, NUMBER 4

Table I. Study demographics and baseline characteristics (intent-to-treat population)

Study 1 Study 2
Efinaconazole Vehicle Total Efinaconazole Vehicle Total
Age, y
Mean, median 52.4, 54.0 51.9, 54.0 52.3, 54.0 50.6, 52.0 50.7, 51.0 50.6, 52.0
Range 20.0-71.0 18.0-70.0 18.0-71.0 18.0-71.0 18.0-70.0 18.0-71.0
Gender
Male 489 (74.5%) 158 (73.8%) 647 (74.4%) 464 (80.0%) 164 (81.6%) 628 (80.4%)
Female 167 (25.5%) 56 (26.2%) 223 (25.6%) 116 (20.0%) 37 (18.4%) 153 (19.6%)
Ethnicity
Hispanic/Latino 71 (10.8%) 31 (14.5%) 102 (11.7%) 122 (21.1%) 46 (22.9%) 168 (21.5%)
Non-Hispanic/Latino 585 (89.2%) 183 (85.5%) 768 (88.3%) 457 (78.9%) 155 (77.1%) 612 (78.5%)
Race
White 425 (64.8%) 140 (65.4%) 565 (64.9%) 552 (90.9%) 164 (81.6%) 686 (87.8%)
Black/African American 36 (5.5%) 7 (3.3%) 43 (4.9%) 34 (5.9%) 21 (10.4%) 55 (7.0%)
American Indian/Alaskan Native 1 (0.2%) 1 (0.5%) 2 (0.2%) 2 (0.3%) 1 (0.5%) 3 (0.4%)
Asian (including Japanese) 189 (28.8%) 63 (29.4%) 252 (29.0%) 11 (1.9%) 6 (3.0%) 17 (2.2%)
Native Hawaiian/Pacific Islander 1 (0.2%) 1 (0.5%) 2 (0.2%) 1 (0.2%) 0 (0.0%) 1 (0.1%)
Other 4 (0.6%) 2 (0.9%) 6 (0.7%) 10 (1.7%) 9 (4.5%) 19 (2.4%)
Percent of affected toenail
Mean, median 36.7, 40.0 36.8, 40.0 36.7, 40.0 36.2, 35.0 36.7, 40.0 36.3, 40.0
Range 20.0-50.0 20.0-50.0 20.0-50.0 20.0-60.0 20.0-50.0 20.0-60.0
No. of affected nontarget toenails
Mean, median 2.8, 3.0 2.8, 3.0 2.8, 3.0 2.7, 3.0 2.8, 3.0 2.8, 3.0
Range 0.0-5.0 0.0-5.0 0.0-5.0 0.0-5.0 0.0-5.0 0.0-5.0

predominantly male (74.4% and 80.4%, respec-
tively). The majority of patients were white (64.9%
and 87.8%, respectively), although a substantial
number of Asian patients were in study 1 from
participation of 33 Japanese sites (Table I).
The mean area of target toenail involvement was
36.7% and 36.3% (studies 1 and 2, respectively) and the
mean number of affected nontarget toenails was 2.8 in
each study. There were no significant or clinically
meaningful differences between treatment groups for
demographics or baseline characteristics (Table I).
Overall, 1436 (86.8%) patients completed the
48-week treatment and 1420 (85.8%) patients
completed the 4-week follow-up. A total of 235
(14.2%) patients discontinued early because of patient
request (98, 41.7%), lost to follow-up (78, 33.2%),
AEs (33, 14.0%), protocol violation (7, 3.0%), other
(17, 7.2%), worsening condition (1, 0.5%), and
pregnancy (1, 0.5%) (Fig 1).
Efficacy
Primary efficacy end point. At week 52, 17.8%
(study 1) and 15.2% (study 2) of patients had a
complete cure on efinaconazole compared with
3.3% and 5.5%, respectively, of patients on vehicle
(both P \.001) (Fig 2).
Secondary and supportive efficacy end
points. At week 52, 55.2% (study 1) and 53.4%
(study 2) of patients achieved mycologic cure on
efinaconazole compared with 16.8% (study 1) and
16.9% (study 2) on vehicle (both P \.001) (Fig 3).
More patients treated with efinaconazole (study 1:
26.4% and study 2: 23.4%) achieved a complete or
almost complete cure compared with vehicle
(study 1: 7.0% and study 2: 7.5%; both P \ .001).
At week 52, 35.7% (study 1) and 31.0% (study 2) of
patients on efinaconazole had treatment success
(\10% clinical involvement) compared with
11.7% (study 1) and 11.9% (study 2) on vehicle
(P \ .001). The proportion of patients who had
treatment success increased, based on defining
clinical involvement as less than or equal to 10%,
less than or equal to 5%, and less than or equal to
0% (Fig 4). Mean unaffected new toenail growth
(study 1: 5.0 mm, study 2: 3.8 mm) was greater for
efinaconazole than vehicle (study 1: 1.6 mm, study
2: 0.9 mm; P \ .001).
Fig 5 shows successful treatment in 2 patients.
These patients had 40% to 45% involvement at
baseline. One patient was assessed as complete
cure (0%) at week 52, the other as almost complete
cure (# 5% clinical involvement).
Safety
Efinaconazole AE rates were similar to vehicle
(study 1: 66% vs 61%, study 2: 64.5% vs 58.5%)
(Table II). They were generally mild (study 1: 45.5%
vs 44.3%, study 2: 61.0% vs 60.6%) or moderate
(study 1: 50.0% vs 53.8%, study 2: 35.1% vs 37.3%) in
604 Elewski et al J AM ACAD DERMATOL
APRIL 2013

Fig 2. Primary efficacy end point (complete cure) over 52 weeks for efinaconazole (study 1:
N = 656, study 2: N = 580) versus vehicle (study 1: N = 214, study 2: N = 201) (intent-to-treat
population, last observation carried forward).

Fig 3. Secondary end point (mycologic cure) at week 52 for efinaconazole (study 1: N = 656,
study 2: N = 580) versus vehicle (study 1: N = 214, study 2: N = 201) (intent-to-treat population,
last observation carried forward).

severity, not related to study drug (study 1: 91.8% vs
98.6%, study 2: 92.7% vs 96.9%), and resolved with-
out sequelae (study 1: 83.6% vs 83.8%, study 2: 80.3%
vs 80.5%).
The rate of discontinuations as a result of AEs was
low for efinaconazole while higher than vehicle
(study 1: 3.2% vs 0.5%, study 2: 1.9% vs 0%). The
most common AEs leading to study discontinuation
were treatment related and associated with the
application site (application site dermatitis and
vesicles).
Yet, efinaconazole was not associated with red-
ness, swelling, burning, itching, or vesiculation, and
localized skin reactions were similar to vehicle. Thus,
J AM ACAD DERMATOL Elewski et al 605
VOLUME 68, NUMBER 4

Fig 4. Treatment success (percent affected toenail area) at week 52 efinaconazole versus
vehicle (intent-to-treat population).

Fig 5. Representative clinical photographs from 2 patients with moderate (40%-45% involve-
ment) distal lateral subungual onychomycosis at baseline treated with efinaconazole for 48
weeks shown, at baseline, week 24, and week 52 (compete cure [subject A] and almost
complete cure [subject B] at week 52).

although more patients on efinaconazole discontin- vehicle. There were no clinically meaningful
ued treatment as a result of application site dermatitis changes from baseline in laboratory or vital sign
and vesicles, the overall AE rates did not differ from measurements for either treatment group.
606 Elewski et al J AM ACAD DERMATOL
APRIL 2013

Table II. Analysis of treatment-emergent adverse events reported by more than 2% of patients in at least
1 study (safety patients)
Study 1 Study 2
N (%) Efinaconazole (N = 653) Vehicle (N = 213) Efinaconazole (N = 574) Vehicle (N = 200)
No. of patients who reported at least 1 TEAE 431 (66.0%) 130 (61.0%) 370 (64.5%) 117 (58.5%)
Individual TEAEs reported by [2% of patients in at least 1 study
Application site dermatitis 23 (3.5%) 0 (0.0%) - -
Application site vesicles 13 (2.0%) 0 (0.0%) 7 (1.2%) 0 (0.0%)
Arthralgia 13 (2.0%) 7 (3.3%) 18 (3.1%) 2 (1.0%)
Back pain 16 (2.5%) 6 (2.8%) 19 (3.3%) 7 (3.5%)
Blood creatinine phosphokinase increased - - 11 (1.9%) 5 (2.5%)
Bronchitis 8 (1.2%) 4 (1.9%) 14 (2.4%) 3 (1.5%)
Contact dermatitis 19 (2.9%) 4 (1.9%) 8 (1.4%) 2 (1.0%)
Eczema 22 (3.4%) 7 (3.3%) - -
Folliculitis 5 (0.8%) 5 (2.3%) - -
Headache 15 (2.3%) 5 (2.3%) 25 (4.4%) 7 (3.5%)
Hypertension 17 (2.6%) 10 (4.7%) 11 (1.9%) 5 (2.5%)
Influenza 16 (2.5%) 8 (3.8%) 10 (1.7%) 1 (0.5%)
Ingrowing nail 17 (2.6%) 1 (0.5%) 11 (1.9%) 2 (1.0%)
Nasopharyngitis 78 (11.9%) 25 (11.7%) 63 (11.0%) 15 (7.5%)
Procedural pain 10 (1.5%) 7 (3.3%) 6 (1.0%) 0 (0.0%)
Sinusitis 30 (4.6%) 4 (1.9%) 17 (3.0%) 5 (2.5%)
Tinea pedis 7 (1.1%) 6 (2.8%) 4 (0.7%) 6 (3.0%)
Upper respiratory tract infection 38 (5.8%) 13 (6.1%) 35 (6.1%) 11 (5.5%)
Urinary tract infection 12 (1.8%) 8 (3.8%) 12 (2.1%) 2 (1.0%)

TEAE, Treatment-emergent adverse event.

DISCUSSION AEs being mild, considered unrelated to treatment,

Although oral treatment of onychomycosis is
standard of care, drug interactions and risk of acute
liver injury limit their use. Yet, the development of
effective topical antifungals has been challenging.
Apart from laser treatment to improve the nail’s
appearance, no new onychomycosis treatments
have been introduced for over 10 years. Difficulties
in formulating topical treatments to penetrate the
nail and reach the site of infection in the nail bed may
have hampered their development.22-24 Poor nail
penetration may be a function of physiochemical
properties, including lipophilicity and keratin bind-
ing, and formulation.25-28
In 2 studies, efinaconazole 10% solution was
significantly more effective than vehicle in treating
DLSO, without requiring debridement. The results
were 2- to 3-fold greater than in studies of other
topical antifungals. Complete cure rates were within
the range of oral itraconazole and mycologic cure
rates were within range of both oral therapies.12,13
When efficacy was defined as complete or almost
complete cure ( # 5% clinical involvement), re-
sponse rates increased by a factor of 48% to 54%.
Minimal visible difference was noted between nails
rated as almost complete or complete cures (Fig 5).
The safety and tolerability profile of efinacona-
zole was similar to vehicle, with the most common
and resolvable. A small proportion of patients re-
ceiving efinaconazole (2%-3%) were more likely to
discontinue than those receiving vehicle (0%-0.5%),
mainly as a result of application site events.
We speculate that complete cure rates (a regula-
tory standard) may underestimate the clinical value
of efinaconazole, given that toenails require up to 78
weeks to grow cleanly, whereas our studies were
52 weeks.29,30 Treatment success rates of 40% to 45%
(# 10% clinical involvement), along with the up-
ward slope of complete cure rates both suggest that
a substantial proportion of patients were heading
toward a complete cure. An alternative predictor
may be mycologic cure, assuming that once it is
achieved clinical cure follows.31
The onychomycosis recurrence rates of 33.7% and
11.9% reported for itraconazole and terbinafine,
respectively,32 suggest potential for efinaconazole
maintenance treatment, although the risk-benefit
profile is unknown. Being a topical solution, systemic
absorption is low, reducing the likelihood of drug
interactions and acute liver injury (Jo et al and Crean
et al, unpublished data, October 2012).
Generalizability of these studies may be limited
from using carefully selected patients and controlled
methods. Participants were older, with mild or
moderate disease, seen over a fixed duration.
J AM ACAD DERMATOL
VOLUME 68, NUMBER 4
These studies do not provide data in children, or
those with severe disease. It is unknown whether
continued improvement would occur with either
longer treatment or follow-up. Nor has efinacona-
zole been studied in combination with oral antifun-
gal treatments.
Overall, in 2 well-controlled studies, efinacona-
zole 10% solution, the first triazole antifungal
developed for DLSO, provided an effective and
well-tolerated treatment. It may be the first topical
treatment for DLSO that can be considered a viable
alternative to oral treatments.
The authors acknowledge the contribution of the fol-
lowing principal investigators:
For study 1: Raza Aly, PhD, San Francisco, Calif; Kirk A.
Barber, MD, Calgary, Alberta, Canada; Elizabeth
Billingsley, MD, Hershey, Pa; Alicia Bucko, DO, JD,
Albuquerque, NM; Daniel A. Carrasco, MD, Austin, Tex;
Scott Clark, MD, Longmont, Colo; Aditya K. Gupta, MD,
PhD, London, Ontario, Canada; Robert Haber, MD, South
Euclid, Ohio; Charles Hudson, MD, Evansville, Ind; Terry
M. Jones, MD, College Station, Tex; John Scott Kasteler,
MD, Louisville, Ky; Rod A. Kunynetz, MD, Barrie, Ontario,
Canada; Anne M. Loebl, MD, FAAD, Augusta, Ga; Keith H.
Loven, MD, CPI, Goodlettsville, Tenn; Verlan ‘‘Tracy’’
Marshall, DPM, Phoenix, Ariz; Brock McConnehey, DO,
CPI, Boise, Idaho; Jose Mendez, DO, Miami, Fla; Alan
Menter, MD, Dallas, Tex; Stephen Miller, MD, San Antonio,
Tex; Eugene Monroe, MD, Milwaukee, Wis; Serena Mraz,
MD, Vallejo, Calif; Walter K. Nahm, MD, PhD, San Diego,
Calif; Michael J. Noss, MD, Cincinnati, Ohio; Eugene
Pascarella, DPM, Altamonte Springs, Fla; Yves Poulin,
MD, FRCPC, Quebec City, Quebec, Canada; Les A.
Rosoph, MD, North Bay, Ontario, Canada; Ronald C.
Savin, MD, New Haven, Conn; Stacy R. Smith, MD, Del
Mar, CA; James A. Solomon, MD, PhD, Ormond Beach, Fla;
Daniel M. Stewart, DO, Clinton Township, Mich; Leonard J.
Swinyer, MD, Salt Lake City, Utah; Darryl P. Toth, MD,
Windsor, Ontario, Canada; Norman R. Wasel, MD,
Edmonton, Alberta, Canada; Jonathan S. Weiss, MD,
Snellville, Ga; Patricia Westmoreland, MD, Greenville, SC;
David C. Wilson, MD, Lynchburg, Va; Tracey C. Vlahovic,
DPM, Philadelphia, Pa; Carole Hazan, MD, New Hyde
Park, NY; Akihiro Tominaga, Hokkaido, Japan; Kazuhiro
Yamada, Hokkaido, Japan; Takashi Uesugi, Hokkaido,
Japan; Hiroko Koizumi, Hokkaido, Japan; Masahito
Chiba, Hokkaido, Japan; Fumihiro Kato, Hokkaido,
Japan; Osamu Oikawa, Hokkaido, Japan; Yoshiko Itoh,
Hokkaido, Japan; Osamu Takeda, Hokkaido, Japan;
Kiyomitsu Yamanaka, Hokkaido, Japan; Atsuyuki
Igarashi, Tokyo, Japan; Akio Taneda, Tokyo, Japan;
Toshio Kusunoki, Tokyo, Japan; Ichiro Nakasu,
Kanagawa, Japan; Tomohiko Matsuyama, Tokyo, Japan;
Naoko Hattori, Tokyo, Japan; Hiroto Kitahara, Tokyo,
Japan; Takuro Katoh, Saitama, Japan; Tetsuo Matsuda,
Fukuoka, Japan; Akihiko Shimizu, Fukuoka, Japan; Hiroe
Kiryu, Fukuoka, Japan; Masahiro Kusuhara, Fukuoka,
Elewski et al 607
Japan; Tatsufumi Yamano, Fukuoka, Japan; Akitoshi
Hatamoto, Fukuoka, Japan; Kazunori Urabe, Fukuoka,
Japan; Katsutaro Nishimoto, Nagasaki, Japan; Kazuyoshi
Yamashiro, Okinawa, Japan; Takao Kamiyama, Okinawa,
Japan; Takashi Kinjo, Okinawa, Japan; Motoyoshi Maruno,
Okinawa, Japan; Meisei Ryo, Okinawa, Japan; Tadashi
Higa, Okinawa, Japan; Toyoko Inazumi, Tokyo, Japan.
For study 2: Lorne E. Albrecht, MD, Surrey, British
Columbia, Canada; Ashish C. Bhatia, MD, Naperville, Ill;
Robert Brodell, MD, Warren, Ohio; Suzanne Bruce, MD,
Houston, Tex; Jennifer Clay Cather, MD, Dallas, Tex; Fran
E. Cook-Bolden, MD, New York, NY; Lesley Davidson, MD,
Mt Pleasant, SC; Michael Donahue, MD, Wilmington, NC;
David P. Fivenson, MD, Ann Arbor, Mich; Paul S. Gillum,
MD, Norman, Okla; Michael H. Gold, MD, Nashville, Tenn;
Kenneth G. Gross, MD, San Diego, Calif; Wayne P. Gulliver,
MD, St John’s, Newfoundland, Canada; Fasahat H.
Hamzavi, MD, Fort Gratiot, Mich; Holly Hake Harris, MD,
South Bend, Ind; Michael Jarratt, MD, Austin, Tex; Robert
Kaylor, DPM, Evansville, Ind; Steven Kempers, MD,
Fridley, Minn; Mark Ling, MD, PhD, Newnan, Ga; Aida
Lugo-Somolinos, MD, Chapel Hill, NC; Charles W. Lynde,
MD, Markham, Ontario, Canada; Robert T. Matheson, MD,
Portland, Ore; Diane McConnehey, DO, CPI, Nampa,
Idaho; Robert Nossa, MD, Verona, NJ; Kim A. Papp, MD,
Waterloo, Ontario, Canada; Elyse Rafal, MD, Stony Brook,
NY; Mani Raman, MD, Richmond Hill, Ontario, Canada;
Alexander Reyzelman, DPM, San Francisco, Calif; Douglas
N. Robins, MD, Jacksonville, Fla; Michael A. Schneider,
MD, Germantown, Tenn; Harry H. Sharata, MD, PhD,
Madison, Wis; Howard L. Sofen, MD, Los Angeles, Calif;
Kenneth Stein, MD, Santa Rosa, Calif; Dow Stough, MD,
Hot Springs, Ark; James M. Swinehart, MD, Denver, Colo;
Jerry K. L. Tan, MD, Windsor, Ontario, Canada; John Toole,
MD, Winnipeg, Manitoba, Canada; John H. Tu, MD,
Rochester, NY; Beatrice Wang, MD, Westmount, Quebec,
Canada; William P. Werschler, MD, Spokane, Wash; Hector
Wiltz, MD, CCTI, Miami, Fla; Darryl Wong, MD, Oceanside,
Calif.
In addition, we thank Jeffrey Sugarman, MD, PhD
(Santa Rosa, Calif), for acting as medical monitor and
John N. Quiring, PhD (QST Consultations Ltd, Allendale,
Mich), for performing statistical analyses.
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