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 North America LLC, Abbott Laboratories, Amgen, Astellas
Birmingham School of Medicinea; Northwest Cutaneous Re- Pharma US Inc, Celgene Corp, DUSA Pharmaceuticals, Galderma
search Specialists, Portlandb; San Antonio Podiatry Associatesc; Laboratories LP, and Genetech Inc, and an investigator for
Department of Dermatology, Eastern Virginia Medical Schoold; Abbott Laboratories, Amgen, Basliea, Celgene Corp, Lilly and
Department of Dermatology, Teikyo University School of Med- Company, Galderma Laboratories LP, Graceway Pharmaceuticals
icine, Tokyoe; Kaken Pharmaceutical Co Ltd, Kyotof and Tokyog; LLC, and Intendis Inc. Dr Pollak was an advisor to Valeant
Dow Pharmaceutical Sciences Inc, (a division of Valeant Phar- Dermatology, a subsidiary of Valeant Pharmaceuticals North
maceuticals North America LLC) Petalumah; and Valeant Phar- America LLC. Drs Elewski, Watanabe, Rich, Pariser, and Pollak
maceuticals North America LLC, Bridgewater.i were all investigators in the efinaconazole studies. Dr Senda and
Supported by Valeant Pharmaceuticals North America LLC, Bridge- Mr Ieda are employees and stockholders in Kaken Pharmaceu-
water, NJ. Editorial assistance was provided by Brian Bulley, ticals Co Ltd. Drs Ramakrishna, Pillai, Olin, and Ms Smith are
MSc, of Inergy Limited, whose fees were paid by Valeant employees and stockholders in Valeant Pharmaceuticals North
Pharmaceuticals North America LLC. America LLC.
Disclosure: Dr Elewski was an advisor to Valeant Dermatology, a Accepted for publication October 8, 2012.
subsidiary of Valeant Pharmaceuticals North America LLC. Dr Reprint requests: Boni E. Elewski, MD, Department of
Watanabe was a consultant to Kaken Pharmaceuticals Co Ltd, Dermatology, University of Alabama at Birmingham School of
Hisamitsu Pharmaceutical Co Inc, and Sato Pharmaceutical Co Medicine, EFH 414, 1530 3rd Ave S, Birmingham, AL
Ltd. Dr Rich was an investigator with Anacor, Celtic Pharma, 35294-0009. E-mail: beelewski@aol.com.
Cipher Pharmaceuticals, Nitric Bio Inc, and Promius Pharma LLC, Published online November 22, 2012.
and an advisor for Valeant Dermatology, a subsidiary of Valeant 0190-9622/$36.00
Pharmaceuticals North America LLC. Dr Pariser was a consultant Ó 2012 by the American Academy of Dermatology, Inc.
to Valeant Dermatology, a subsidiary of Valeant Pharmaceuticals 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 J AM ACAD DERMATOL
APRIL 2013

Fig 1. Schematic profile of study disposition.

Study assessment intent-to-treat population included all patients

The primary efficacy end point was the propor- randomized and dispensed study drug. The safety
tion of patients achieving complete cure at week 52 population included all patients who received at least
(4-week posttreatment visit) defined as 0% clinical 1 dose of study drug, and 1 postbaseline assessment.
involvement of the target toenail and mycologic cure Efficacy end points were compared using
(negative potassium hydroxide examination, and Cochran-Mantel-Haenszel tests (stratified by analysis
negative fungal culture of the target toenail sample). center) at a 5% significance level. Unaffected new
Secondary end points were: mycologic cure, treat- toenail growth was analyzed using a 2-way variance
ment success (\10% clinical involvement of the analysis. Missing efficacy data were imputed using
target toenail), complete or almost complete cure the last observation carried forward method; no
(# 5% clinical involvement and mycologic cure), and imputations for missing safety data were performed.
unaffected toenail growth (change from baseline). All AEs were recorded and classified using the
All secondary end points were assessed at week 52. Medical Dictionary for Regulatory Activities
Supportive efficacy end points included treatment (MedDRA version 12.1). A Fisher exact test was
success (0%-# 10% clinical involvement of the target used to compare the incidences of treatment-
toenail), change in the number of affected nontarget emergent AEs and treatment-related AEs occurring
toenails, change in quality of life, and target toenail with frequencies 1% or higher.
growth. A study investigator assessed the outcomes
at each visit. RESULTS
Safety assessments included monitoring and Patients
recording of adverse events (AEs) until week 52. There were 1655 patients with DLSO randomized
(study 1: 870, study 2: 785) at 118 sites: United States
Study oversight (study 1: 34, study 2: 36), Canada (study 1: 7, study 2: 8),
The studies were conducted in accordance with and Japan (study 1: 33). Studies were conducted from
the ethical principles specified in the Declaration of December 2009 to September 2011 (study 1: DPSI-IDP-
Helsinki and in compliance with requirements of 108-P3-01) and October 2011 (study 2: DPSI-IDP-108-
local regulatory committees. All patients provided P3-02) (ClinicalTrials.gov numbers NCT01008033
written informed consent. and NCT01007708). Patients were randomized to
efinaconazole 10% solution (study 1: 656, study 2:
Statistical analysis 583) or vehicle (study 1: 214, study 2: 202) (Fig 1).
Data from each trial were analyzed separately At baseline, patient mean age was 52.3 and 50.6
using software (SAS, SAS Institute Inc, Cary, NC). The 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- 16.9% (study 2) on vehicle (both P \.001) (Fig 3).
tively). The majority of patients were white (64.9% More patients treated with efinaconazole (study 1:
and 87.8%, respectively), although a substantial 26.4% and study 2: 23.4%) achieved a complete or
number of Asian patients were in study 1 from almost complete cure compared with vehicle
participation of 33 Japanese sites (Table I). (study 1: 7.0% and study 2: 7.5%; both P \ .001).
The mean area of target toenail involvement was At week 52, 35.7% (study 1) and 31.0% (study 2) of
36.7% and 36.3% (studies 1 and 2, respectively) and the patients on efinaconazole had treatment success
mean number of affected nontarget toenails was 2.8 in (\10% clinical involvement) compared with
each study. There were no significant or clinically 11.7% (study 1) and 11.9% (study 2) on vehicle
meaningful differences between treatment groups for (P \ .001). The proportion of patients who had
demographics or baseline characteristics (Table I). treatment success increased, based on defining
Overall, 1436 (86.8%) patients completed the clinical involvement as less than or equal to 10%,
48-week treatment and 1420 (85.8%) patients less than or equal to 5%, and less than or equal to
completed the 4-week follow-up. A total of 235 0% (Fig 4). Mean unaffected new toenail growth
(14.2%) patients discontinued early because of patient (study 1: 5.0 mm, study 2: 3.8 mm) was greater for
request (98, 41.7%), lost to follow-up (78, 33.2%), efinaconazole than vehicle (study 1: 1.6 mm, study
AEs (33, 14.0%), protocol violation (7, 3.0%), other 2: 0.9 mm; P \ .001).
(17, 7.2%), worsening condition (1, 0.5%), and Fig 5 shows successful treatment in 2 patients.
pregnancy (1, 0.5%) (Fig 1). These patients had 40% to 45% involvement at
baseline. One patient was assessed as complete
Efficacy cure (0%) at week 52, the other as almost complete
Primary efficacy end point. At week 52, 17.8% cure (# 5% clinical involvement).
(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 Safety
(both P \.001) (Fig 2). Efinaconazole AE rates were similar to vehicle
Secondary and supportive efficacy end (study 1: 66% vs 61%, study 2: 64.5% vs 58.5%)
points. At week 52, 55.2% (study 1) and 53.4% (Table II). They were generally mild (study 1: 45.5%
(study 2) of patients achieved mycologic cure on vs 44.3%, study 2: 61.0% vs 60.6%) or moderate
efinaconazole compared with 16.8% (study 1) and (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 most common AEs leading to study discontinuation
98.6%, study 2: 92.7% vs 96.9%), and resolved with- were treatment related and associated with the
out sequelae (study 1: 83.6% vs 83.8%, study 2: 80.3% application site (application site dermatitis and
vs 80.5%). vesicles).
The rate of discontinuations as a result of AEs was Yet, efinaconazole was not associated with red-
low for efinaconazole while higher than vehicle ness, swelling, burning, itching, or vesiculation, and
(study 1: 3.2% vs 0.5%, study 2: 1.9% vs 0%). The 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 and resolvable. A small proportion of patients re-
standard of care, drug interactions and risk of acute ceiving efinaconazole (2%-3%) were more likely to
liver injury limit their use. Yet, the development of discontinue than those receiving vehicle (0%-0.5%),
effective topical antifungals has been challenging. mainly as a result of application site events.
Apart from laser treatment to improve the nail’s We speculate that complete cure rates (a regula-
appearance, no new onychomycosis treatments tory standard) may underestimate the clinical value
have been introduced for over 10 years. Difficulties of efinaconazole, given that toenails require up to 78
in formulating topical treatments to penetrate the weeks to grow cleanly, whereas our studies were
nail and reach the site of infection in the nail bed may 52 weeks.29,30 Treatment success rates of 40% to 45%
have hampered their development.22-24 Poor nail (# 10% clinical involvement), along with the up-
penetration may be a function of physiochemical ward slope of complete cure rates both suggest that
properties, including lipophilicity and keratin bind- a substantial proportion of patients were heading
ing, and formulation.25-28 toward a complete cure. An alternative predictor
In 2 studies, efinaconazole 10% solution was may be mycologic cure, assuming that once it is
significantly more effective than vehicle in treating achieved clinical cure follows.31
DLSO, without requiring debridement. The results The onychomycosis recurrence rates of 33.7% and
were 2- to 3-fold greater than in studies of other 11.9% reported for itraconazole and terbinafine,
topical antifungals. Complete cure rates were within respectively,32 suggest potential for efinaconazole
the range of oral itraconazole and mycologic cure maintenance treatment, although the risk-benefit
rates were within range of both oral therapies.12,13 profile is unknown. Being a topical solution, systemic
When efficacy was defined as complete or almost absorption is low, reducing the likelihood of drug
complete cure ( # 5% clinical involvement), re- interactions and acute liver injury (Jo et al and Crean
sponse rates increased by a factor of 48% to 54%. et al, unpublished data, October 2012).
Minimal visible difference was noted between nails Generalizability of these studies may be limited
rated as almost complete or complete cures (Fig 5). from using carefully selected patients and controlled
The safety and tolerability profile of efinacona- methods. Participants were older, with mild or
zole was similar to vehicle, with the most common moderate disease, seen over a fixed duration.
J AM ACAD DERMATOL Elewski et al 607
VOLUME 68, NUMBER 4

These studies do not provide data in children, or Japan; Tatsufumi Yamano, Fukuoka, Japan; Akitoshi
those with severe disease. It is unknown whether Hatamoto, Fukuoka, Japan; Kazunori Urabe, Fukuoka,
continued improvement would occur with either Japan; Katsutaro Nishimoto, Nagasaki, Japan; Kazuyoshi
longer treatment or follow-up. Nor has efinacona- Yamashiro, Okinawa, Japan; Takao Kamiyama, Okinawa,
Japan; Takashi Kinjo, Okinawa, Japan; Motoyoshi Maruno,
zole been studied in combination with oral antifun-
Okinawa, Japan; Meisei Ryo, Okinawa, Japan; Tadashi
gal treatments.
Higa, Okinawa, Japan; Toyoko Inazumi, Tokyo, Japan.
Overall, in 2 well-controlled studies, efinacona-
For study 2: Lorne E. Albrecht, MD, Surrey, British
zole 10% solution, the first triazole antifungal Columbia, Canada; Ashish C. Bhatia, MD, Naperville, Ill;
developed for DLSO, provided an effective and Robert Brodell, MD, Warren, Ohio; Suzanne Bruce, MD,
well-tolerated treatment. It may be the first topical Houston, Tex; Jennifer Clay Cather, MD, Dallas, Tex; Fran
treatment for DLSO that can be considered a viable E. Cook-Bolden, MD, New York, NY; Lesley Davidson, MD,
alternative to oral treatments. Mt Pleasant, SC; Michael Donahue, MD, Wilmington, NC;
David P. Fivenson, MD, Ann Arbor, Mich; Paul S. Gillum,
The authors acknowledge the contribution of the fol- MD, Norman, Okla; Michael H. Gold, MD, Nashville, Tenn;
lowing principal investigators: Kenneth G. Gross, MD, San Diego, Calif; Wayne P. Gulliver,
For study 1: Raza Aly, PhD, San Francisco, Calif; Kirk A. MD, St John’s, Newfoundland, Canada; Fasahat H.
Barber, MD, Calgary, Alberta, Canada; Elizabeth Hamzavi, MD, Fort Gratiot, Mich; Holly Hake Harris, MD,
Billingsley, MD, Hershey, Pa; Alicia Bucko, DO, JD, South Bend, Ind; Michael Jarratt, MD, Austin, Tex; Robert
Albuquerque, NM; Daniel A. Carrasco, MD, Austin, Tex; Kaylor, DPM, Evansville, Ind; Steven Kempers, MD,
Scott Clark, MD, Longmont, Colo; Aditya K. Gupta, MD, Fridley, Minn; Mark Ling, MD, PhD, Newnan, Ga; Aida
PhD, London, Ontario, Canada; Robert Haber, MD, South Lugo-Somolinos, MD, Chapel Hill, NC; Charles W. Lynde,
Euclid, Ohio; Charles Hudson, MD, Evansville, Ind; Terry MD, Markham, Ontario, Canada; Robert T. Matheson, MD,
M. Jones, MD, College Station, Tex; John Scott Kasteler, Portland, Ore; Diane McConnehey, DO, CPI, Nampa,
MD, Louisville, Ky; Rod A. Kunynetz, MD, Barrie, Ontario, Idaho; Robert Nossa, MD, Verona, NJ; Kim A. Papp, MD,
Canada; Anne M. Loebl, MD, FAAD, Augusta, Ga; Keith H. Waterloo, Ontario, Canada; Elyse Rafal, MD, Stony Brook,
Loven, MD, CPI, Goodlettsville, Tenn; Verlan ‘‘Tracy’’ NY; Mani Raman, MD, Richmond Hill, Ontario, Canada;
Marshall, DPM, Phoenix, Ariz; Brock McConnehey, DO, Alexander Reyzelman, DPM, San Francisco, Calif; Douglas
CPI, Boise, Idaho; Jose Mendez, DO, Miami, Fla; Alan N. Robins, MD, Jacksonville, Fla; Michael A. Schneider,
Menter, MD, Dallas, Tex; Stephen Miller, MD, San Antonio, MD, Germantown, Tenn; Harry H. Sharata, MD, PhD,
Tex; Eugene Monroe, MD, Milwaukee, Wis; Serena Mraz, Madison, Wis; Howard L. Sofen, MD, Los Angeles, Calif;
MD, Vallejo, Calif; Walter K. Nahm, MD, PhD, San Diego, Kenneth Stein, MD, Santa Rosa, Calif; Dow Stough, MD,
Calif; Michael J. Noss, MD, Cincinnati, Ohio; Eugene Hot Springs, Ark; James M. Swinehart, MD, Denver, Colo;
Pascarella, DPM, Altamonte Springs, Fla; Yves Poulin, Jerry K. L. Tan, MD, Windsor, Ontario, Canada; John Toole,
MD, FRCPC, Quebec City, Quebec, Canada; Les A. MD, Winnipeg, Manitoba, Canada; John H. Tu, MD,
Rosoph, MD, North Bay, Ontario, Canada; Ronald C. Rochester, NY; Beatrice Wang, MD, Westmount, Quebec,
Savin, MD, New Haven, Conn; Stacy R. Smith, MD, Del Canada; William P. Werschler, MD, Spokane, Wash; Hector
Mar, CA; James A. Solomon, MD, PhD, Ormond Beach, Fla; Wiltz, MD, CCTI, Miami, Fla; Darryl Wong, MD, Oceanside,
Daniel M. Stewart, DO, Clinton Township, Mich; Leonard J. Calif.
Swinyer, MD, Salt Lake City, Utah; Darryl P. Toth, MD, In addition, we thank Jeffrey Sugarman, MD, PhD
Windsor, Ontario, Canada; Norman R. Wasel, MD, (Santa Rosa, Calif), for acting as medical monitor and
Edmonton, Alberta, Canada; Jonathan S. Weiss, MD, John N. Quiring, PhD (QST Consultations Ltd, Allendale,
Snellville, Ga; Patricia Westmoreland, MD, Greenville, SC; Mich), for performing statistical analyses.
David C. Wilson, MD, Lynchburg, Va; Tracey C. Vlahovic,
DPM, Philadelphia, Pa; Carole Hazan, MD, New Hyde REFERENCES
Park, NY; Akihiro Tominaga, Hokkaido, Japan; Kazuhiro 1. Scher RK, Coppa LM. Advances in the diagnosis and treatment
Yamada, Hokkaido, Japan; Takashi Uesugi, Hokkaido, of onychomycosis. Hosp Med 1998;34:11-20.
Japan; Hiroko Koizumi, Hokkaido, Japan; Masahito 2. Crissey JT. Common dermatophyte infections: a simple diag-
Chiba, Hokkaido, Japan; Fumihiro Kato, Hokkaido, nostic test and current management. Postgrad Med 1998;103:
Japan; Osamu Oikawa, Hokkaido, Japan; Yoshiko Itoh, 191-2, 197-200, 205.
Hokkaido, Japan; Osamu Takeda, Hokkaido, Japan; 3. Kumar S, Kimball AB. New antifungal therapies for the treat-
Kiyomitsu Yamanaka, Hokkaido, Japan; Atsuyuki ment of onychomycosis. Expert Opin Investig Drugs 2009;18:
727-34.
Igarashi, Tokyo, Japan; Akio Taneda, Tokyo, Japan;
4. Scher RK. Onychomycosis: therapeutic update. J Am Acad
Toshio Kusunoki, Tokyo, Japan; Ichiro Nakasu,
Dermatol 1999;40(Suppl):S21-6.
Kanagawa, Japan; Tomohiko Matsuyama, Tokyo, Japan; 5. Elewski BE, Charif MA. Prevalence of onychomycosis in pa-
Naoko Hattori, Tokyo, Japan; Hiroto Kitahara, Tokyo, tients attending a dermatology clinic in northeastern Ohio for
Japan; Takuro Katoh, Saitama, Japan; Tetsuo Matsuda, other conditions. Arch Dermatol 1997;133:1172-3.
Fukuoka, Japan; Akihiko Shimizu, Fukuoka, Japan; Hiroe 6. Drake LA, Patrick DL, Fleckman P, Andr J, Baran R, Haneke E,
Kiryu, Fukuoka, Japan; Masahiro Kusuhara, Fukuoka, et al. The impact of onychomycosis on quality of life:
608 Elewski et al J AM ACAD DERMATOL
APRIL 2013

development of an international onychomycosis question- 21. Sparavigna A, Setaro M, Frisenda L. Physical and microbiolog-
naire to measure patient quality of life. J Am Acad Dermatol ical properties of a new nail protective medical device. J Plastic
1999;41:189-96. Dermatol 2008;4:5-12.
7. Scher RK. Onychomycosis: a significant medical disorder. J Am 22. Baran R, Kaoukhov A. Topical antifungal drugs for the treat-
Acad Dermatol 1996;35(Suppl):S2-5. ment of onychomycosis: an overview of current strategies for
8. Lubeck DP, Patrick DL, McNulty P, Fifer SK, Birnbaum J. Quality of monotherapy and combination therapy. J Eur Acad Dermatol
life of persons with onychomycosis. Qual Life Res 1993;2:341-8. Venereol 2005;19:21-9.
9. Whittam LR, Hay RJ. The impact of onychomycosis on quality 23. Lecha M, Effendy I, Feuilhade de Chauvin M, Di Chiacchio N,
of life. Clin Exp Dermatol 1997;22:87-9. Baran R. Treatment optionsedevelopment of consensus guide-
10. Reich A, Szepietowski JC. Health-related quality of life in lines. J Eur Acad Dermatol Venereol 2005;19(Suppl):25-33.
patients with nail disorders. Am J Clin Dermatol 2011;12: 24. Murdan S. Drug delivery to the nail following topical applica-
313-20. tion. Int J Pharm 2002;236:1-26.
11. Finch JJ, Warshaw EM. Toenail onychomycosis: current and 25. Baker SJ, Hui X, Maibach HI. Progress on new therapeutics for
future treatment options. Dermatol Ther 2007;20:31-46. fungal nail infections. Ann Rep Med Chem 2005;40:323-34.
12. Sporanox (itraconazole) [package insert]. Titusville, NJ: Janssen 26. Mertin D, Lippold BC. In vitro permeability of the human nail
Pharmaceuticals Inc; 2012. and of a keratin membrane from bovine hooves: influence of
13. Lamisil (terbinafine HCl) [package insert]. East Hanover, NJ: the partition coefficient octanol/water and the water solubility
Novartis Pharmaceuticals Corp; 2012. of drugs on their permeability and maximum flux. J Pharm
14. Tavakkol A, Fellman S, Kianifard F. Safety and efficacy of Pharmacol 1997;49:30-4.
oral terbinafine in the treatment of onychomycosis: analysis 27. Kobayashi Y, Komatsu T, Sumi M, Numajiri S, Miyamoto M,
of the elderly subgroup in improving results in Kobayashi D, et al. In vitro permeation of several drugs
onychomycosis-concomitant Lamisil and debridement through the human plate: relationship between physicochem-
(IRON-CLAD), an open-label, randomized trial. Am J Geriatr ical properties and nail permeability of drugs. Eur J Pharm Sci
Pharmacother 2006;4:1-13. 2004;21:471-7.
15. Arrese JE, Pierard GE. Treatment failures and relapses in 28. Tatsumi Y, Yokoo M, Senda H, Kakehi K. Therapeutic efficacy of
onychomycosis: a stubborn clinical problem. Dermatology topically applied KP-103 against experimental tinea unguium
2003;207:255-60. in guinea pigs in comparison with amorolfine and terbinafine.
16. Darkes MJ, Scott LJ, Goa KL. Terbinafine: a review of its use in Antimicrob Agents Chemother 2002;46:3797-801.
onychomycosis in adults. Am J Clin Dermatol 2003;4:39-65. 29. Werschler WP, Bondar G, Armstrong D. Assessing treatment
17. Warshaw EM, Fett DD, Bloomfield HE, Grill JP, Nelson DB, outcomes in toenail onychomycosis clinical trials. Am J Clin
Quintero V, et al. Pulse versus continuous terbinafine for Dermatol 2004;5:145-52.
onychomycosis: a randomized, double-blind, controlled trial. 30. De Cuyper C. Long-term outcomes in the treatment of toenail
J Am Acad Dermatol 2005;53:578-84. onychomycosis. Br J Dermatol 1999;141:15-20.
18. Baran R, Sigurgeirsson B, de Berker D, Kaufman R, Lecha M, 31. Elewski BE, Ghannoum MA, Mayser P, Gupta AK, Korting HC,
Faergemann J, et al. A multicenter, randomized, controlled Shouey RJ, et al. Efficacy, safety and tolerability of topical
study of the efficacy, safety and cost-effectiveness of a combi- terbinafine nail solution in patients with mild-to-moderate
nation therapy with amorolfine nail lacquer and oral terbinafine toenail onychomycosis: results from three randomized
compared with oral terbinafine alone for the treatment of studies using double-blind vehicle-controlled and open-label
onychomycosis with matrix involvement. Br J Dermatol 2007; active-controlled designs. J Eur Acad Dermatol Venereol
157:149-57. December doi: 10.1111/j.1468-3083.2011.04373.x. Published
19. Fungal nail infections: diagnosis and management [editorial]. online December 20, 2011.
Prescrire Int 2009;18:26-30. 32. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail
20. Gupta AK, Joseph WS. Ciclopirox 8% nail lacquer in the onychomycosis caused by dermatophytes after successful
treatment of onychomycosis of the toenails in the United treatment with systemic antifungal agents. J Am Acad
States. J Am Podiatr Med Assoc 2000;90:495-501. Dermatol 2010;62:411-4.