Efinaconazole 10% solution in the treatment of toenailonychomycosis: Two phase III multicenter,

randomized, double-blind studiesBoni 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

From

Bi

se

D

D

ic

D

m

m

Supp

w

M

Ph

Discl

su

W

H

Lt

C

an

Ph

to

600

Background: Onychomycosis is a common nail infection, often resulting in nail plate damage anddeformity. 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 firsttriazole 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 dailyfor 48 weeks, with 4-week posttreatment follow-up. Debridement was not performed. The primary endpoint was complete cure rate (0% clinical involvement of target toenail, and both negative potassiumhydroxide 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 forefinaconazole (study 1: 17.8% vs 3.3%, study 2: 15.2% vs 5.5%, P \ .001). Treatment success (percentaffected target toenail [0%-# 10%]) for efinaconazole ranged from 21.3% to 44.8% in study 1 and from17.9% 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 optionsfor onychomycosis. ( J Am Acad Dermatol 2013;68:600-8.)

the Department of Dermatology, University of Alabama at

rmingham School of Medicinea; Northwest Cutaneous Re-

arch Specialists, Portlandb; San Antonio Podiatry Associatesc;

epartment of Dermatology, Eastern Virginia Medical Schoold;

epartment of Dermatology, Teikyo University School of Med-

ine, Tokyoe; Kaken Pharmaceutical Co Ltd, Kyotof and Tokyog;

ow Pharmaceutical Sciences Inc, (a division of Valeant Phar-

aceuticals North America LLC) Petalumah; and Valeant Phar-

aceuticals North America LLC, Bridgewater.i

orted by Valeant Pharmaceuticals North America LLC, Bridge-

ater, NJ. Editorial assistance was provided by Brian Bulley,

Sc, of Inergy Limited, whose fees were paid by Valeant

armaceuticals North America LLC.

osure: Dr Elewski was an advisor to Valeant Dermatology, a

bsidiary of Valeant Pharmaceuticals North America LLC. Dr

atanabe was a consultant to Kaken Pharmaceuticals Co Ltd,

isamitsu Pharmaceutical Co Inc, and Sato Pharmaceutical Co

d. Dr Rich was an investigator with Anacor, Celtic Pharma,

ipher Pharmaceuticals, Nitric Bio Inc, and Promius Pharma LLC,

d an advisor for Valeant Dermatology, a subsidiary of Valeant

armaceuticals North America LLC. Dr Pariser was a consultant

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

� 2012 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2012.10.013

J AM ACAD DERMATOL

VOLUME 68, NUMBER 4Elewski et al 601

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

Distal lateral subungual growth, positive potassium

CAPSULE SUMMARY

d Onychomycosis is a common nailinfection that is difficult to treat andmanage long term. Oral antifungals arelimited by safety concerns and druginteractions, and topical antifungals bymodest efficacy.

d Efinaconazole 10% solution is aneffective treatment for mild to moderateonychomycosis.

d For patients who would prefer anefficacious topical onychomycosistreatment, efinaconazole provides arealistic option.

onychomycosis (DLSO) is acommon and progressivefungal infection of the nailbed, which may extend intothematrix or plate, leading todestruction and deformity oftoenails and, less frequently,fingernails.1,2 Prevalence in-creases with age3-5 and it isassociated with patient dis-tress, disability, and pain.6-10

Onychomycosis is challeng-ing to treat because of slownail growth and difficultiesdelivering treatment to theinfection site.3,11

Phase III studies of oralitraconazole and terbinafine

report complete cure rates of 14% and 38% andmycologic cure rates of 54% and 70%, respec-tively.12,13 Subsequent studies report lower completecure rates.14-17 Oral treatment is limited by druginteractions and risk of acute liver injury (requiringlaboratory monitoring), which is relevant to elderlypatients.18,19

Patients may prefer an efficacious topical treat-ment if there areminimal systemic side effects and nolaboratory monitoring. However, ciclopirox lacquerhas a complete cure rate of 5.5% to 8.5%,12 andmycologic cure rates of 34%.20 It requires frequentnail debridement and residual lacquer removal.21

Thus, we investigated the safety and efficacy ofefinaconazole 10% (wt/wt) solution (IDP-108), thefirst triazole antifungal developed specifically for thetopical treatment of DLSO.

METHODSStudy design

In 2 identical, multicenter, randomized, parallel-group, double-blind, vehicle-controlled studies, pa-tients with mild to moderate toenail DLSO (definedas 20%-50% clinical involvement of the target toenail,without dermatophytomas ormatrix [lunula] involve-ment) were randomized to receive efinaconazole10% solution or vehicle. Eligibility criteria included:18 to 70 years of age, clinical diagnosis of DLSOaffecting at least 1 great toenail, target toenail unin-fected length 3 mm or more (from the proximalnailfold), thickness 3 mm or less, evidence of toenail

hydroxidemicroscopy result,and culture of dermatophyteor mixed dermatophyte/Candida less than or equalto 42 days before baseline.Women of childbearing agewere required to use birthcontrol.

Exclusion criteria included:history of immunosuppres-sion and/or clinical signsindicative of possible immu-nosuppression, known HIVinfection, uncontrolled diabe-tes mellitus, presence oftoenail infection other thandermatophytes, severemocca-sin tinea pedis at screening/

baseline, any disease/condition thatmight have causedtoenail abnormalities or interfered with the evaluation,and previous target toenail surgery. Patients were notexcluded for concomitant drugs that inhibit cyto-chrome P450 3A4.

Enrolled patients were randomized to receiveefinaconazole or vehicle (3:1 ratio) self-appliedonce daily for 48 weeks without debridement, fol-lowed by a treatment-free 4-week follow-up.Treatment was applied to the clean, dry nail platesurface, lateral and proximal nailfolds, hyponychium,and undersurface of the nail plate. Patients wereassessed for efficacy and safety at baseline, 12-weekintervals postbaseline (ie, weeks 12, 24, 36, and 48),and final visit (week 52).

Randomization and maskingStudy drugs were provided in a kit containing

identical masked bottles with a randomization num-ber determined by a computer-generated randomi-zation schedule. Access to the randomizationschedule was permitted after both the databasewas locked and the study unblinded. The investiga-tors, sponsor, investigational center staff, clinicalmonitors, patients, and all other study personnelwere unaware of study drug assignment to individualpatients. In case of a medical emergency where itbecame necessary to know treatment assignment,the identity was made available to the investigator. Ifthe treatment code was broken, the patient wasdiscontinued.

Fig 1. Schematic profile of study disposition.

J AM ACAD DERMATOL

APRIL 2013602 Elewski et al

Study assessmentThe primary efficacy end point was the propor-

tion of patients achieving complete cure at week 52(4-week posttreatment visit) defined as 0% clinicalinvolvement of the target toenail and mycologiccure (negative potassium hydroxide examination,and negative fungal culture of the target toenailsample). Secondary end points were: mycologiccure, treatment success (\10% clinical involvementof the target toenail), complete or almost completecure (# 5% clinical involvement and mycologiccure), and unaffected toenail growth (change frombaseline). All secondary end points were assessed atweek 52.

Supportive efficacy end points included treatmentsuccess (0%-# 10% clinical involvement of the targettoenail), change in the number of affected nontargettoenails, change in quality of life, and target toenailgrowth. A study investigator assessed the outcomesat each visit.

Safety assessments included monitoring andrecording of adverse events (AEs) until week 52.

Study oversightThe studies were conducted in accordance with

the ethical principles specified in the Declaration of

Helsinki and in compliance with requirements oflocal regulatory committees. All patients providedwritten informed consent.

Statistical analysisData from each trial were analyzed separately

using software (SAS, SAS Institute Inc, Cary, NC). Theintent-to-treat population included all patients ran-domized and dispensed study drug. The safetypopulation included all patients who received atleast 1 dose of study drug, and 1 postbaselineassessment.

Efficacy end points were compared usingCochran-Mantel-Haenszel tests (stratified by analy-sis center) at a 5% significance level. Unaffectednew toenail growth was analyzed using a 2-wayvariance analysis. Missing efficacy data were im-puted using the last observation carried forwardmethod; no imputations for missing safety datawere performed.

All AEs were recorded and classified using theMedical Dictionary for Regulatory Activities(MedDRA version 12.1). A Fisher exact test wasused to compare the incidences of treatment-emergent AEs and treatment-related AEs occurringwith frequencies 1% or higher.

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

Study 1 Study 2

Efinaconazole Vehicle Total Efinaconazole Vehicle Total

Age, yMean, median 52.4, 54.0 51.9, 54.0 52.3, 54.0 50.6, 52.0 50.7, 51.0 50.6, 52.0Range 20.0-71.0 18.0-70.0 18.0-71.0 18.0-71.0 18.0-70.0 18.0-71.0

GenderMale 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%)

EthnicityHispanic/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%)

RaceWhite 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 toenailMean, median 36.7, 40.0 36.8, 40.0 36.7, 40.0 36.2, 35.0 36.7, 40.0 36.3, 40.0Range 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 toenailsMean, median 2.8, 3.0 2.8, 3.0 2.8, 3.0 2.7, 3.0 2.8, 3.0 2.8, 3.0Range 0.0-5.0 0.0-5.0 0.0-5.0 0.0-5.0 0.0-5.0 0.0-5.0

J AM ACAD DERMATOL

VOLUME 68, NUMBER 4Elewski et al 603

RESULTSPatients

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 conductedfrom December 2009 to September 2011 (study 1:DPSI-IDP-108-P3-01) and October 2011 (study 2:DPSI-IDP-108-P3-02) (ClinicalTrials.gov numbersNCT01008033 and NCT01007708). Patients wererandomized to efinaconazole 10% solution (study1: 656, study 2: 583) or vehicle (study 1: 214, study 2:202) (Fig 1).

At baseline, patient mean age was 52.3 and 50.6years (studies 1 and 2, respectively). Patients werepredominantly male (74.4% and 80.4%, respec-tively). The majority of patients were white (64.9%and 87.8%, respectively), although a substantialnumber of Asian patients were in study 1 fromparticipation of 33 Japanese sites (Table I).

The mean area of target toenail involvement was36.7% and 36.3% (studies 1 and 2, respectively) andthe mean number of affected nontarget toenailswas 2.8 in each study. There were no significant orclinically meaningful differences between treatmentgroups for demographics or baseline characteristics(Table I).

Overall, 1436 (86.8%) patients completed the48-week treatment and 1420 (85.8%) patients

completed the 4-week follow-up. A total of 235(14.2%) patients discontinued early because of patientrequest (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).

EfficacyPrimary efficacy end point. At week 52, 17.8%

(study 1) and 15.2% (study 2) of patients had acomplete cure on efinaconazole compared with3.3% and 5.5%, respectively, of patients on vehicle(both P\ .001) (Fig 2).

Secondary and supportive efficacy endpoints. At week 52, 55.2% (study 1) and 53.4%(study 2) of patients achieved mycologic cure onefinaconazole compared with 16.8% (study 1) and16.9% (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 oralmost 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) ofpatients on efinaconazole had treatment success(\10% clinical involvement) compared with11.7% (study 1) and 11.9% (study 2) on vehicle(P \ .001). The proportion of patients who hadtreatment success increased, based on definingclinical involvement as less than or equal to 10%,

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-treatpopulation, 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).

J AM ACAD DERMATOL

APRIL 2013604 Elewski et al

less than or equal to 5%, and less than or equal to0% (Fig 4). Mean unaffected new toenail growth(study 1: 5.0 mm, study 2: 3.8 mm) was greater forefinaconazole than vehicle (study 1: 1.6 mm, study2: 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 completecure (0%) at week 52, the other as almost completecure (# 5% clinical involvement).

SafetyEfinaconazole AE rates were similar to vehicle

(study 1: 66% vs 61%, study 2: 64.5% vs 58.5%)

Fig 4. Treatment success (percent affected toenail area) at week 52 efinaconazole versusvehicle (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 48weeks shown, at baseline, week 24, and week 52 (compete cure [subject A] and almostcomplete cure [subject B] at week 52).

J AM ACAD DERMATOL

VOLUME 68, NUMBER 4Elewski et al 605

(Table II). Theywere generallymild (study 1: 45.5% vs44.3%, study 2: 61.0% vs 60.6%) or moderate (study 1:50.0% vs 53.8%, study 2: 35.1% vs 37.3%) in severity,

not related to study drug (study 1: 91.8% vs 98.6%,study 2: 92.7% vs 96.9%), and resolved without seque-lae (study 1: 83.6% vs 83.8%, study 2: 80.3% vs 80.5%).

Table II. Analysis of treatment-emergent adverse events reported by more than 2% of patients in at least1 study (safety patients)

N (%)

Study 1 Study 2

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 studyApplication 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.

J AM ACAD DERMATOL

APRIL 2013606 Elewski et al

The rate of discontinuations as a result of AEs waslow for efinaconazole while higher than vehicle(study 1: 3.2% vs 0.5%, study 2: 1.9% vs 0%). Themost common AEs leading to study discontinuationwere treatment related and associated with the appli-cation site (application site dermatitis and vesicles).

Yet, efinaconazole was not associated with red-ness, swelling, burning, itching, or vesiculation, andlocalized skin reactions were similar to vehicle. Thus,although more patients on efinaconazole discontin-ued treatment as a result of application site dermatitisand vesicles, the overall AE rates did not differ fromvehicle. There were no clinically meaningfulchanges from baseline in laboratory or vital signmeasurements for either treatment group.

DISCUSSIONAlthough oral treatment of onychomycosis is

standard of care, drug interactions and risk of acuteliver injury limit their use. Yet, the development ofeffective topical antifungals has been challenging.Apart from laser treatment to improve the nail’sappearance, no new onychomycosis treatmentshave been introduced for over 10 years. Difficultiesin formulating topical treatments to penetrate thenail and reach the site of infection in the nail bedmayhave hampered their development.22-24 Poor nail

penetration may be a function of physiochemicalproperties, including lipophilicity and keratin bind-ing, and formulation.25-28

In 2 studies, efinaconazole 10% solution wassignificantly more effective than vehicle in treatingDLSO, without requiring debridement. The resultswere 2- to 3-fold greater than in studies of othertopical antifungals. Complete cure rates were withinthe range of oral itraconazole and mycologic curerates were within range of both oral therapies.12,13

When efficacy was defined as complete or almostcomplete cure (# 5% clinical involvement), re-sponse rates increased by a factor of 48% to 54%.Minimal visible difference was noted between nailsrated as almost complete or complete cures (Fig 5).

The safety and tolerability profile of efinacona-zole was similar to vehicle, with the most commonAEs being mild, considered unrelated to treatment,and resolvable. A small proportion of patients re-ceiving efinaconazole (2%-3%) were more likely todiscontinue 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 valueof efinaconazole, given that toenails require up to 78weeks to grow cleanly, whereas our studies were52 weeks.29,30 Treatment success rates of 40% to 45%

J AM ACAD DERMATOL

VOLUME 68, NUMBER 4Elewski et al 607

(# 10% clinical involvement), along with the up-ward slope of complete cure rates both suggest thata substantial proportion of patients were headingtoward a complete cure. An alternative predictormay be mycologic cure, assuming that once it isachieved clinical cure follows.31

The onychomycosis recurrence rates of 33.7% and11.9% reported for itraconazole and terbinafine,respectively,32 suggest potential for efinaconazolemaintenance treatment, although the risk-benefitprofile is unknown. Being a topical solution, systemicabsorption is low, reducing the likelihood of druginteractions and acute liver injury (Jo et al and Creanet al, unpublished data, October 2012).

Generalizability of these studies may be limitedfrom using carefully selected patients and controlledmethods. Participants were older, with mild ormoderate disease, seen over a fixed duration.These studies do not provide data in children, orthose with severe disease. It is unknown whethercontinued improvement would occur with eitherlonger 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 antifungaldeveloped for DLSO, provided an effective andwell-tolerated treatment. It may be the first topicaltreatment for DLSO that can be considered a viablealternative 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; ElizabethBillingsley, 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, SouthEuclid, Ohio; Charles Hudson, MD, Evansville, Ind; TerryM. 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; AlanMenter, 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; EugenePascarella, 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, DelMar, 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 HydePark, NY; Akihiro Tominaga, Hokkaido, Japan; KazuhiroYamada, Hokkaido, Japan; Takashi Uesugi, Hokkaido,Japan; Hiroko Koizumi, Hokkaido, Japan; MasahitoChiba, Hokkaido, Japan; Fumihiro Kato, Hokkaido,Japan; Osamu Oikawa, Hokkaido, Japan; Yoshiko Itoh,Hokkaido, Japan; Osamu Takeda, Hokkaido, Japan;Kiyomitsu Yamanaka, Hokkaido, Japan; AtsuyukiIgarashi, 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; HiroeKiryu, Fukuoka, Japan; Masahiro Kusuhara, Fukuoka,Japan; Tatsufumi Yamano, Fukuoka, Japan; AkitoshiHatamoto, Fukuoka, Japan; Kazunori Urabe, Fukuoka,Japan; Katsutaro Nishimoto, Nagasaki, Japan; KazuyoshiYamashiro, Okinawa, Japan; Takao Kamiyama, Okinawa,Japan; Takashi Kinjo, Okinawa, Japan; Motoyoshi Maruno,Okinawa, Japan; Meisei Ryo, Okinawa, Japan; TadashiHiga, Okinawa, Japan; Toyoko Inazumi, Tokyo, Japan.

For study 2: Lorne E. Albrecht, MD, Surrey, BritishColumbia, Canada; Ashish C. Bhatia, MD, Naperville, Ill;Robert Brodell, MD, Warren, Ohio; Suzanne Bruce, MD,Houston, Tex; Jennifer Clay Cather, MD, Dallas, Tex; FranE. Cook-Bolden, MD, NewYork, 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; RobertKaylor, DPM, Evansville, Ind; Steven Kempers, MD,Fridley, Minn; Mark Ling, MD, PhD, Newnan, Ga; AidaLugo-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; DouglasN. 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; HectorWiltz, MD, CCTI, Miami, Fla; Darryl Wong, MD, Oceanside,Calif.

J AM ACAD DERMATOL

APRIL 2013608 Elewski et al

In addition, we thank Jeffrey Sugarman, MD, PhD(Santa Rosa, Calif), for acting as medical monitor andJohn N. Quiring, PhD (QST Consultations Ltd, Allendale,Mich), for performing statistical analyses.

REFERENCES

1. Scher RK, Coppa LM. Advances in the diagnosis and treatment

of onychomycosis. Hosp Med 1998;34:11-20.

2. Crissey JT. Common dermatophyte infections: a simple diag-

nostic test and current management. Postgrad Med 1998;103:

191-2, 197-200, 205.

3. Kumar S, Kimball AB. New antifungal therapies for the treat-

ment of onychomycosis. Expert Opin Investig Drugs 2009;18:

727-34.

4. Scher RK. Onychomycosis: therapeutic update. J Am Acad

Dermatol 1999;40(Suppl):S21-6.

5. Elewski BE, Charif MA. Prevalence of onychomycosis in pa-

tients attending a dermatology clinic in northeastern Ohio for

other conditions. Arch Dermatol 1997;133:1172-3.

6. Drake LA, Patrick DL, FleckmanP, Andr J, Baran R, Haneke E, et al.

The impact of onychomycosis on quality of life: development

of an international onychomycosis questionnaire to measure

patient quality of life. J Am Acad Dermatol 1999;41:189-96.

7. Scher RK. Onychomycosis: a significant medical disorder. J Am

Acad Dermatol 1996;35(Suppl):S2-5.

8. LubeckDP, PatrickDL,McNulty P, Fifer SK, BirnbaumJ.Quality of

life of persons with onychomycosis. Qual Life Res 1993;2:341-8.

9. Whittam LR, Hay RJ. The impact of onychomycosis on quality

of life. Clin Exp Dermatol 1997;22:87-9.

10. Reich A, Szepietowski JC. Health-related quality of life in

patients with nail disorders. Am J Clin Dermatol 2011;12:313-20.

11. Finch JJ, Warshaw EM. Toenail onychomycosis: current and

future treatment options. Dermatol Ther 2007;20:31-46.

12. Sporanox (itraconazole) [package insert]. Titusville, NJ: Janssen

Pharmaceuticals Inc; 2012.

13. Lamisil (terbinafine HCl) [package insert]. East Hanover, NJ:

Novartis Pharmaceuticals Corp; 2012.

14. Tavakkol A, Fellman S, Kianifard F. Safety and efficacy of

oral terbinafine in the treatment of onychomycosis: analysis

of the elderly subgroup in improving results in

onychomycosis-concomitant Lamisil and debridement

(IRON-CLAD), an open-label, randomized trial. Am J Geriatr

Pharmacother 2006;4:1-13.

15. Arrese JE, Pierard GE. Treatment failures and relapses in

onychomycosis: a stubborn clinical problem. Dermatology

2003;207:255-60.

16. Darkes MJ, Scott LJ, Goa KL. Terbinafine: a review of its use in

onychomycosis in adults. Am J Clin Dermatol 2003;4:39-65.

17. Warshaw EM, Fett DD, Bloomfield HE, Grill JP, Nelson DB,

Quintero V, et al. Pulse versus continuous terbinafine for

onychomycosis: a randomized, double-blind, controlled trial.

J Am Acad Dermatol 2005;53:578-84.

18. Baran R, Sigurgeirsson B, de Berker D, Kaufman R, Lecha M,

Faergemann J, et al. A multicenter, randomized, controlled

study of the efficacy, safety and cost-effectiveness of a combi-

nation therapywith amorolfine nail lacquer and oral terbinafine

compared with oral terbinafine alone for the treatment of

onychomycosis with matrix involvement. Br J Dermatol 2007;

157:149-57.

19. Fungal nail infections: diagnosis and management [editorial].

Prescrire Int 2009;18:26-30.

20. Gupta AK, Joseph WS. Ciclopirox 8% nail lacquer in the

treatment of onychomycosis of the toenails in the United

States. J Am Podiatr Med Assoc 2000;90:495-501.

21. Sparavigna A, Setaro M, Frisenda L. Physical and microbiolog-

ical properties of a new nail protective medical device. J Plastic

Dermatol 2008;4:5-12.

22. Baran R, Kaoukhov A. Topical antifungal drugs for the treat-

ment of onychomycosis: an overview of current strategies for

monotherapy and combination therapy. J Eur Acad Dermatol

Venereol 2005;19:21-9.

23. Lecha M, Effendy I, Feuilhade de Chauvin M, Di Chiacchio N,

Baran R. Treatment optionsedevelopment of consensus guide-

lines. J Eur Acad Dermatol Venereol 2005;19(Suppl):25-33.

24. Murdan S. Drug delivery to the nail following topical applica-

tion. Int J Pharm 2002;236:1-26.

25. Baker SJ, Hui X, Maibach HI. Progress on new therapeutics for

fungal nail infections. Ann Rep Med Chem 2005;40:323-34.

26. Mertin D, Lippold BC. In vitro permeability of the human nail

and of a keratin membrane from bovine hooves: influence of

the partition coefficient octanol/water and the water solubility

of drugs on their permeability and maximum flux. J Pharm

Pharmacol 1997;49:30-4.

27. Kobayashi Y, Komatsu T, Sumi M, Numajiri S, Miyamoto M,

Kobayashi D, et al. In vitro permeation of several drugs

through the human plate: relationship between physicochem-

ical properties and nail permeability of drugs. Eur J Pharm Sci

2004;21:471-7.

28. Tatsumi Y, Yokoo M, Senda H, Kakehi K. Therapeutic efficacy of

topically applied KP-103 against experimental tinea unguium

in guinea pigs in comparison with amorolfine and terbinafine.

Antimicrob Agents Chemother 2002;46:3797-801.

29. Werschler WP, Bondar G, Armstrong D. Assessing treatment

outcomes in toenail onychomycosis clinical trials. Am J Clin

Dermatol 2004;5:145-52.

30. De Cuyper C. Long-term outcomes in the treatment of toenail

onychomycosis. Br J Dermatol 1999;141:15-20.

31. Elewski BE, Ghannoum MA, Mayser P, Gupta AK, Korting HC,

Shouey RJ, et al. Efficacy, safety and tolerability of topical

terbinafine nail solution in patients with mild-to-moderate

toenail onychomycosis: results from three randomized

studies using double-blind vehicle-controlled and open-label

active-controlled designs. J Eur Acad Dermatol Venereol

December doi: 10.1111/j.1468-3083.2011.04373.x. Published

online December 20, 2011.

32. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail

onychomycosis caused by dermatophytes after successful

treatment with systemic antifungal agents. J Am Acad

Dermatol 2010;62:411-4.