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`JEADV
`
`AIMS & SCOPE
`
`The Journal of the European Academy ofDermatology and Venereology (JEADV) publishes articles of general and practical interest in
`the field of dermatology and venereology including clinical and basic science topics, as well as research with practical implications. It
`does so through editorials, review and practice articles, original papers of general interest, short reports, letters to the editor, features
`and EADV announcements.
`
`JEADV EDITORIAL BOARD
`
`Editor-in-Chief
`Jean—Paul ORTONNE (FR)
`Hopital L’Archet 2 — Dermatologie
`B1’ 3079
`06202 Nice Cedex 3 — France
`E-mail: ortonne@unice.fr
`
`Assistant Editors
`Lorenzo CERRONI (AT)
`Tliicrry PASSERON (FR)
`
`Editorial Staff
`Maryse CLAPPIER
`E-mail: maryse.clappier@unice.fr
`
`Statistical Advisor
`Alan KELLY (IE)
`
`Founding Editors
`Torello LOTTI (IT)
`Derek FREEDMAN (IE)
`
`Honorary Editors
`Otto BRAUN-FALCO (DE)
`Jean CIVATTE (FR)
`John HARRIS (GB)
`Stefania JABLONSKA (PL)
`Emiliano PANCONESI (IT)
`
`EADV LEADERSHIP
`
`Executive Committee
`Jana HERCOGOVA (CZ)
`President
`
`Erwin TSCHACHLER (AT)
`President-elect
`Frank POWELL (IE)
`Past President
`Carle PAUL (FR)
`Secretary~General
`Jorgen RONNEVIG (NO)
`Treasurer
`
`Ljiljana MEDENICA (RS)
`Representative of the Board
`Martin ROCKEN (DE)
`Representative of the Board
`
`JEADV Editorial Board
`Jeffrey D. BERNHARD (US)
`Thomas BIEBER (DE)
`Lasse R. BRAATHEN (CH)
`Jeffrey CALLEN (US)
`Francisco CAMACHO MARTINEZ (ES)
`Stephano CHIMENTI (IT)
`Boni
`ELEWSKI (US)
`Dan FORSEA (RO)
`Jean Jacques GROB (FR)
`Aditya Kumar GUPTA (CA)
`Rudolf HAPPLE (DE)
`Jana HERCOGOVA (CZ)
`Andreas D. KATSAMBAS (GR)
`Stephen I. KATZ (US)
`Peter Karl KOHL (DE)
`Jean—Marie LACHAPELLE (BE)
`Mark LEBWOHL (US)
`Joseph L. PACE (MT)
`Lawrence C. PARISH (US)
`Gerald E. PIERARD (BE)
`Frank C. POWELL (IE)
`Thomas RUZICKA (DE)
`Berthold RZANY (DE)
`Robert A. SCHWARTZ (US)
`H. Peter SOYER (AU)
`Georg STINGL (AT)
`Kristian THESTRURPEDERSEN (DK)
`Ronni WOLF (IL)
`
`JEADV Advisory Board
`Robert BARAN (PR)
`Ulrike ELUME-PEYTAVI (DE)
`Michael BOFFA (MT)
`Luca G. BORRADORI (CH)
`Sarah BRENNER (IL)
`Thomas DIEPGEN (DE)
`James FERGUSON (GB)
`Ramon GRIMALT (ES)
`Roderick James HAY (GB)
`Karl IIOLUBAR (AT)
`Demetris IOANNIDES (GR)
`Jean KANITAKIS (FR)
`Gertruud KREKELS (NL)
`Michael LANDTIIALLER (DE)
`Thomas LUGER (DE)
`Hans MERK (DE)
`H.A. Martino NEUMANN (NL)
`Carle PAUL (FR)
`Hubert PEHAIVI BERGER (AT)
`Francoise POOT (BE)
`Albert—Adrien RAMELET (CH)
`Johannes RING (DE)
`Jorgen SERUP (DK)
`Erwin TSCHACHLER (AT)
`Giovanna ZAMBRUNO (IT)
`
`Board of Directors
`Agustin ALOMAR (ES)
`Sibel ALPER (TR)
`Josette ANDRE (BE)
`Christina ANTONIOU (GR)
`Petr ARENBERGER (CZ)
`Jonathan BARKER (GB)
`Peter BLOCH (CH)
`Michael BOFFA (MT)
`Maryse BRANDENBURGER (LU)
`Magnus BRUZF. (SE)
`Matilda BYLAITE (LT)
`Piergiacomo CALZAVARA«PINTON (IT)
`Pavel CHERNYSHOV (UA)
`Florence CORGIBET (FR)
`Rodica COSGAREA (RO)
`Americo FIGUEIREDO (PT)
`Herbert HONIGSMANN (AT)
`Jana KAZANDJIEVA (BG)
`Lajos KEMENY (IIU)
`Kiilli KINGO (EE)
`Alexey KUBANOV (RU)
`
`Board of Directors (cont.)
`Julien LAMBERT (BE)
`Claus LUTZOVV—I‘IOLM (NO)
`Branka MARINOVIC (HR)
`Pauline MARREN (IE)
`Ljiljana MBDENICA (RS)
`Martino NEUMANN (NL)
`Juraj PEC (SK)
`Ramon PUJOL (ES)
`Tapio RANTANIEN (Ill)
`Michael REUSCH (DE)
`Martin ROCKEN (DE)
`Franco RONGlOLIiTTI (IT)
`Silvestrs RUBINS (LV)
`SedefSAHIN (TR)
`Carmen SALAVASTRU (RO)
`Dimitris SOTIRIADIS (GR)
`Jacek SZEPIETOWSKI (PL)
`Kristin TIIORISDOTTIR (IS)
`Georgios VAKIS (CY)
`Catherine VAN MONTFRANS (NL)
`
`This material was copied
`at the NLM anrd may be
`Subject Ufiflwpyright Laws
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`
`JHADV
`
`CONTENTS
`
`March 2013 Volume 27, Issue 3
`
`
`
`REVIEW ARTICLES
`
`Terbinafine in the treatment of dermatophyte toenail onychomycosis: a meta-analysis of efficacy for
`continuous and intermittent regimens
`A.K. Gupta, M. Paquet, F. Simpson, A. Tavakkol
`
`Cellulite’s aetiology: a review
`M. de la Casa Almeida, C. Suarez Serrano, I. Rebollo Roldan, ].]. ]ime’nez Rejano
`
`
`
`ORIGINAL ARTICLES
`
`Vitiligo patients from India (Mumbai) show differences in clinical, demographic and autoantibody
`profiles compared to patients in western countries
`V. Pradhan, M. Patwardhan, V. Thakkar, V. Kharkar, U. Khopkar, K. G/wsh, A.P. Weetman,
`DJ. Gawkrodger, E.H. Kemp
`
`Efficacy, safety and tolerability of topical terbinafine 11ail solution i11 patients with mild-to-moderate
`toenail onychomycosis: results from three randomized studies using double-bli11d vehicle-controlled
`and open-label active-controlled designs
`B.E. Elewski, M.A. Glimmoum, P. Mayser, A.K. Gupta, H.-C. Korting, RJ. Shoaey, D.R. Baker, P.A. Rich,
`M. Ling, S. Hugot, B. Damaj, I. Nyirady, K. T/iangavelu, M. Notter, A. Parneix-Spake, B. Sigurgeirssorl
`
`Childhood mycosis fungoides: a report of 20 cases from Turkey
`K.D. Yazganoglu, Z. Topkarci, N. Buyuklmbarzi, C. Baykal
`
`Facial sebum affects the development of acne, especially the distribution of inflammatory acne
`C. W. Choi, ]. W. Choi, K.C. Park, S. W. Youn
`
`Comparative study of treatment efficacy and the incidence of post—inflammatory hyperpigmentation
`with different degrees of irradiation using two different quality-switched lasers for removing solar
`lentigines on Asian skin
`K. Negishi, H. Akita, S. Tanaka, Y. Yokoyama, S. Wakamatsu, K. Matszmaga
`
`Report of 457 sporotrichosis cases from Jilin province, northeast China, a serious endemic region
`Y. Song, S.-S. Li, S.-X. Zhong, Y.-Y. Liu, L. Yao, S.-S. Huo
`
`Association of psoriasis with the VEGF gene polymorphism in the northern Polish population
`M. Zablotna, M. Sobjanek, B. Nedoszytko, M. Lange, D. Kozicka, I. Glen, ]. Roszkiewicz
`
`A randomized two-sided placebo-controlled study on the efficacy and safety of atmospheric
`non-thermal argon plasma for pruritus
`I. Heinlin, G. Isbary, W. Stolz, F. Zeman, M. Landtlialer, G. Morfill, T. Shimizu, ].L. Zimmermann,
`S. Karrer
`
`The effects of systemic isotretinoin and antibiotic therapy on the microbial floras in patients with acne
`vulgaris
`P. Y. Basak, E.S. Cetin, I. Giirses, A.G. Ozseverz
`
`Clinical significance of serum retinol binding protein-4 levels in patients with systemic sclerosis
`T. To)/ama, Y. Asano, T. Takahashi, N. Aozasa, K. Akamata, S. Nada, T. Taniguchi, Y. Ic//zimum,
`H. Sumida, Z. Tamaki, Y. Masai, Y. Tada, M. Sugaya, S. Sato, T. Kadono
`
`267
`
`273
`
`279
`
`287
`
`295
`
`301
`
`307
`
`313
`
`319
`
`324
`
`332
`
`337
`
`_ CFAD v. Anacor, |PR2015-01776 ®
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`
`IEADV
`
`JEADV
`
`Journal oftlze European Academy ofDermatology and Venereology
`
`Published on behalf of the European Academy of Dermatology and Venereology
`Legal Premises: EADV, Via F. Pelli 2, CH 6900 Lugano, Switzerland
`Administrative Office: EADV, Avenue General de Gaulle 38, B-1050 Brussels, Belgium
`Tel: +32 2 650 00 90; Fax: +32 2 650 O0 98
`Email: oflice@eadv.org;Web: www.eadv.org
`VAT 110.: BE 476 222 191
`
`For submission instructions, subscription and all other information visit:
`www.jeadv.com
`
`DISCLAIMER
`
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`cannot be held responsible for errors or any consequences arising from the use of
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`Venereology and Editors, neither does the publication ofadvertisements constitute any
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`SUBSCRIPTIONS
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`the European Academy of Dermatology and
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`ISSN 0926-9959 (Print)
`ISSN 1468-3083 (Online)
`
`COVER ILLUSTRATION
`
`Lymphocytes aligned in epidermal basal
`(Case 12) (HE X400)
`
`layer, purpura in the papillary dermis
`
`This material was -to-piael
`at‘ the NLtz.i1 and may be
`Su U‘jzECTJ US {aspyright Laws
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`CFAD V. Anacor, |PR2015-01776
`ANACOR EX. 2045 - 4/15
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`IEADV
`
`
`345
`
`351
`
`356
`
`365
`
`370
`
`376
`
`383
`
`387
`
`391
`
`393
`
`395
`
`395
`
`Resveratrate protects human skin from damage due to repetitive ultraviolet irradiation
`Y. Wu, L.—L. Iia, Y.-N. Zlzeng, X.—G. Xu, Y.-]. Luo, B. Wang, ].Z.S. Chen, X.-H. Gao, H.-D. Chen, M. Matsui,
`Y.-H. Li
`
`Estimation of tissue osteopontin levels before and after different traditional therapeutic modalities in
`psoriatic patients
`N.H. El-Eishi, D. Kadry, R.A. Hegazy, L. Rushed
`
`A patch testing and cross-sensitivity study of carbamazepine-induced severe cutaneous adverse drug
`reactions
`
`Y.-T. Lin, Y.-C. Chang, R.C.—Y. Hui, C.-H. Yang, H.-C. Ho, S.-I. Hung, W.-H. Chung
`
`Status of oxidative stress on lesional skin surface of plantar warts
`O. Aricun, P. Ozturk, E.B. Kzirutas, V. Unsal
`
`Self-declared sensitive skin in China: a coinmunity-based study in three top metropolises
`F. Xu, 8. Yan, M. Wu, F. Li, Q. Sun, W. Lai, X. Slzen, N. Ralzhali, C. Taieb, J. Xu
`
`Mucocutaneous manifestations of HIV-infected patients in the era of HAART in Guangxi Zhuang
`Autonomous Region, China
`I. Han, W.H. Lun, Z.H. Merig, K. Huang, Y. Mao, W. Zhu, S. Lian
`
`
`
`SHORT REPORTS
`
`Determinants of social anxiety and social avoidance in psoriasis outpatients
`G. Schneider, G. Heuft, I. Hockmmm
`
`The influence of systemic therapy on the serum levels of IL-6 and IL8 in pemphigus
`vulgaris
`H. Mortazavi, F. Babczeijcziidczglii, M. Akbarzadeh, N. Rezaei, A.A. Amirzargar, M. Daneshpazhooh,
`A. Ialali, Z. Hallaji
`
`
`
`LETTERS TO THE EDITOR
`
`Classification of acne scars is difficult even for acne experts
`A.Y. Finlay, V. Torres, 8. Kcmg, V. Bettoli, B. Dreno, C.L. Goh, H. Gollnick, On belialfoftlze Global
`Alliance
`
`Mucocutaneous telangiectasia — it’s the tip of the iceberg
`B. C. Biickle, M. Shoukier, S. Kazalfiifl, N. T. Sepp
`
`Increased levels of COX-2 and oral lichen planus
`P.D. Pigatto, F. Spadari, G.P. Bombeccari, G. Guzzi
`
`Reply to increased levels of COX-2 and oral lichen planus by P.D. Pigatto, F. Spaderi, G.P. Bombeccari,
`G. Guzzi by Danielsson et a1.
`K. Danielsson, M. Ebrahimi, Y.B. Walzlin, K. Nylander, L. Boldrup
`
`
`397 Forthcoming events
`
`398 Announcement
`
`This material was cupied
`at the NLM and may be
`Subject U5 {is-pyright Laws
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`CFAD v. Anacor, |PR20‘|5-01776
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`
`IEADV
`
`ONLINE ARTICLES
`
`The following articles are available exclusively online as part of this volume
`and issue at: www.jeadv.com
`
`
`ORIGINAL ARTICLES
`
`e263 2012 European guideline for the management of anogenital warts
`C.].N. Lacey, S.C. Woodhall, A. Wikstrom, I. Ross
`
`e271 Biomarkers of oxidative stress in epidermis of Tunisian pemphigus foliaceus patients
`0. Abida, B. Gargouri, R. Ben Mansour, M. Mseddi—Djemal, A. Masmoadi, M. Ben Ayed, M. Ahdelmoula,
`H. Turki, S. Lassoued, H. Masmoudi
`
`e276 Quality of life in alopecia areata: a disease-specific questionnaire
`G. Fabbrocini, L. Panariello, V. De Vita, C. Vincenzi, C. Laaro, D. Nappo, F. Ayala, A. Tosti
`
`e282 Differences between objective efficacy and perceived efficacy in patients with palmar hyperhidrosis
`treated with either botulinum toxin or endoscopic thoracic sympathectomy
`M.A. Alvarez, I. Ruano, F.]. Gomez, E. Casas, C. Baamonde, A. Salvatierra, ].C. Moreno
`
`e289 Lipoprotein-associated phospholipase A, level in patients with Beh<;et’s disease
`A. Orem, S. Yayli, D.A. Arzca, B. Akcan, F.B. Yiicesan, S. Bahadir
`
`e294 Evaluation of tourists’ UV exposure in Paris
`E. Mahé, M.P. Corréa, S. Godin-Beekmann, M. Haeffelin, F. Iégou, P. Saiag, A. Beaachet
`
`e305 Efficacy and safety of acitretin in three fixed doses of 25, 35 and 50 mg in adult patients with severe
`plaque type psoriasis: a randomized, double blind, parallel group, dose ranging study
`8. Dogra, A. Iain, A.]. Kanwar
`
`e312 A simple scoring system for the diagnosis of palmo-plantar pigmented skin lesions by digital
`dermoscopy analysis
`P. Ruhegni, G. Cevenini, N. Nami, G. Argenziano, T. Saida, M. Burroni, P. Quaglino, R. Bono,
`R. Hofmann-Wellenhofi M. Fimiani
`
`e320 Correlation among metallothionein expression, intratumoural macrophage infiltration and the risk of
`metastasis in human cutaneous malignant melanoma
`Emri, K. Egervari, T. Varvolgyi, D. Rozsa, E. Mike, B. Dezso, I. Veres, G. Mehes, G. Emri,
`
`Remenyik
`
`e328 Effect of skin pH for wrinkle formation on Asian: Korean, Vietnamese and Singaporean
`Y.C. hing, E.]. Kim, ].C. Cho, K.D. Suh, G. W. Nam
`
`e333 Effect of physician dress style on patient confidence
`A. Maruani, I. Leger, B. Girazidean, M. Naouri, E. Le Bidre, M. Samimi, M. Delage
`
`e338 Hereditary angioedema: first report of the Brazilian registry and challenges
`A.S. Grumach, S.O.R. Valle, E. Toledo, D. de Moraes Vasconcelos, M.M.S. Villela, E. Mansonr, ].A. Pinto,
`R.A. Campos, A.T. Franco, On behalfofgroup interested on HAE (GINHA)
`
`e345 Freckles and solar lentigines have different risk factors in Caucasian women
`K. Ezzedine, E. Manger, I. Latreille, R. Idid, D. Malvy, F. Griiber, P. Golan, S. Hercberg, E. Tschachler, C. Guinot
`
`e357 Birhombic flap, a modified bilobed flap, for repair of nasal defect
`A.M. Skaria
`
`e363 Randomized, double-blind, placebo-controlled study of safety and efficacy of miltefosine in
`antihistamine-resistant chronic spontaneous urticaria
`M. Magerl, M. Rather, T. Bieher, T. Biedermann, I. Brasch, R. Dominicns, N. Hzmzelmann, T. Jakob,
`V. Mahler, G. Popp, K. Schiikel, R. Schlingensiepen, I. Schmitt, F. Sielienhaar, ].C. Simon, P. Stauhach,
`B. Wedi, C. Weidner, M. Maurer
`
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`CFAD v. Anacor, |PR2015—O1776
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`ANACOR EX. 2045 - 6/15
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`[HA I) V
`
`e370 The relationship between oxidative stress, smoking and the clinical severity of psoriasis
`S. Emre, A. Metin, D.D. Demirseren, S. Kilic, S. Isikoglu, O. Erel
`
`e376 Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a
`phase II, multicenter, randomized, double~blind, placebo-controlled, parallel-group, dose-comparison
`study
`K.A. Papp, R. Knufmann, D. Tlzaci, C. Hu, D. Sutherland, P. Rohane
`
`e384 Efficacy and safety of systemic methotrexate vs. acitretin in psoriasis patients with significant
`palmoplantar involvement: a prospective, randomized study
`A.B. Ianagond, A.]. Kanwar, S. Hamla
`
`e390 IL-13: a marker of chromium contact allergy
`L.E.A.M. Martins, V.M.S. Reis
`
`e394 Pretherapeutic laboratory findings, extent of metastasis and choice of treatment as prognostic
`markers in ocular melanoma~ a single ce11tre experience
`N. Sclzicher, G. Edellzauser, K. Harmcmkaya, K. Schindler, A. Gleiss, H. Pehamberger, C. Hoeller
`
`e400 Efficacy and safety of diphenylcyclopropenone among Chinese patients with steroid resistant and
`extensive alopecia areata
`N.M. Luk, L.S. Clziu, K.C. Lee, C. T.S. Chan, V. W. Y. Lee, M. Chang, Y.K. Lam, H.C. Lee
`
`
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`SHORT REPORTS
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`e406 Nevus oligemicus: a case series
`A. Batalla, A. Flérez, C. Posada, C. De la 'I'orre
`
`e410 Methotrexate for treatment of lichen planus: old drug, new indication
`A.]. Kanwar, D. De
`
`e414 Correlation of photographic images from the Leeds revised acne grading system with a six-category
`global acne severity scale
`].K.L. Tan, X. Zhang, E. Jones, L. Bulger
`
`e420 DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function
`variants
`
`A.H. Ziyab, W. Karrnaus, ]. W. Holloway, H. Zhang, S. Ewart, S.H. Arshad
`
`e424 Counselling on sun protection, a survey of French paediatricians
`E. Make’, R. Assathiany, F. Fay-Clzatelard, M. Taylor, S. Bouvresse, M. Navel, P. Saiag, B. Chevallier,
`A. Beauchet
`
`e428 French teenagers and artificial tanning
`E. Tella, A. Beauchet, I. Vouldoukis, I.-F. Séi, P. Beaulieu, M.—L. Sigal, E. Mahe’
`
`
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`LETTERS TO THE EDITOR
`
`e433 Oculocutaneous albinism and skin cancer risk
`
`H.C. de Vijlder, H. M. de Vzjlder, H.A.M. Neumann
`
`e434 Why there is a wide difference in the clinical and mycological results in different onychomycosis
`clinical studies
`
`A. Shemer, R. Scher, R. Farhi, R. Magun, R. Daniel
`
`e435 Urticaria-like follicular mucinosis: four new cases of a controversial entity
`E. Cinotti, D. Basso, P. Donati, A. Parodi, F. Rongioletti
`
`This mate—riaIwa5smpied
`*“‘*“*"‘L'*"a“*“"aY'="E
`Subject US {Lu-wright‘ Laws
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`V. AnaCCr,
`ANACOR EX. 2045 — 7/15
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`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2045 - 7/15
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`DOI: 10.1111/j.1468-3083.2011.04373.X ]EADV
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`ORlGlNAL ARTICLE
`
`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
`
`B.E. Elewski,T'* M.A. Ghannoumft P. Mayser,§ A.K. Gupta,’ H.—C. Korting,” R.J. shouey,“
`D.R. Baker,§§ P.A. Rich," M. Ling,”T S. Hugot,*** B. Damaj,§§§ J. Nyirady,'rl-""l‘ K. Thangavelu,***
`M. Notter,*** A. Parneix—Spake,"’*'l‘ B. Sigurgeirssonfifi
`
`"Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, USA
`*Center for Medical Mycology, Case Western Reserve University, Cleveland and University Hospitals of Cleveland, Cleveland,
`OH, USA
`§Center of Dermatology and Andrology, Justus Liebig University, Giessen, Germany
`'Division of Dermatology, Department of Medicine, University of Toronto, Canada
`“Department of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany
`**Harrisonburg Foot Clinic, Harrisonburg, VA, USA
`“Allergy, Asthma & Dermatology Research Center, LLC, Lake Oswego, OR, USA
`'-"Oregon Dermatology and Research Center, Portland, OR, USA
`T”Medaphase lnc., Newnan, GA, USA
`***Novartis Pharma AG, Basel, Switzerland
`'3§§NexMed (USA), lnc., San Diego, CA, USA
`":"Novartis Pharmaceuticals Corp., East Hanover, NJ, USA
`ttltoepartmem of Dermatology, University of Iceland, Reykjavik, Iceland
`‘Correspondence: B.E. Elewski. E-mail: beelewski@aol.com
`
`Abstract
`
`Background Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis.
`Objective To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer.
`Methods Subjects with mild-to—moderate toe onychomycosis (25% to 375% nail-involvement, matrix uninvolved)
`were randomized to receive either TNS or vehicle in two double-blind studies, and to TNS or amorolfine in an active-
`controlled, open-label study. Primary endpoint was complete cure (no residual clinical
`involvement and negative
`mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH
`microscopy and negative culture) and clinical effectiveness (s10% residual-involvement and negative mycology) at
`week 52.
`
`Results Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher
`with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different
`for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy
`was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important
`prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and
`clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment
`duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well-tolerated.
`Conclusion Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to
`achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of
`nail involvement of study population.
`Received: 29 May 2011; Accepted: 10 November 2011
`
`Conflict of interest
`
`H.C. Korting has previously collaborated with Novartis in the development of topicais containing terbinafine, and
`with Galderma concerning amorolfin-containing preparations. Drs‘. P. Mayser, R. Shouey, A. Gupta and 5.
`
`/
`
`IEADV 2013, 27, 287-294
`
`Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology
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`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2045 - 8/15
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`© 2011 The Authors
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2045 - 8/15
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`

`
`288
`Elewski et al.
`
`Sigurgeirsson have no conflict of interests. S. Hugot, M. Notter, K. Thangavelu, A. Parneix-Spake and J. Nyirady are
`employees of Novartis. Drs' B.E. Elewski, P. Rich and M. Ling have received research grant fund from Novartis for
`the performing of the study. Dr B. Damaj
`is an employee of NeXMed (USA),
`Inc. Dr D. Baker was a principal
`investigator at one of
`the research sites. Dr M. Ghannoum has accepted as a consultant
`for Novartis
`Pharmaceuticals.
`
`Funding sources
`Novartis Pharma AG, Basel, Switzerland.
`
`Introduction
`
`Onychomycosis is the most common cause of nail dystrophy,
`affecting 12-13% of the general population,1’7 and 25% of the
`geriatric and diabetic popL1lation.6’8’9 The disease can be painful or
`cause functional disability, psychosocial problems and compro-
`mised quality of life.‘°"2
`Topical treatments are generally reserved for mild cases of ony-
`chomycosis as they are less effective than systemic oral therapy
`due to reasons including poor penetration, less depot effect and
`less depot area.” However, systemic therapy is not recommended
`in some patients due to the risk of possible drug—drug interactions
`and patient co-morbidities.”’15 Because of the slow growth rate of
`toenails, treatment of toe onychomycosis is more challenging than
`finger onychomycosis and it may take up to 18 months of therapy
`to achieve clearance.]("2° Although topical agents like amorolfine
`5% (marketed in Europe) and ciclopirox 8% (available in Europe
`and US) formulated as lacquers have improved drug delivery to
`nails,2I cure rates are lower than with systemic therapy and
`re-infection or relapse often occurs, as is the case with oral anti-
`fungal tl1erapy.”’l6’22’23
`Terbinafine, a synthetic allylamine is a well-established broad-
`spectrum anti-fungal drug,“ with unique clinical efficacy combined
`with good tolerability.17’25 Based on the reservoir effect observed
`with a film-forming solution of terbinafine l%26’27 (allowing for a
`single-application treatment of interdigital
`tinea pedis), a nail
`solution [topical
`terbinafine HC1 nail
`solution (TNS)] was
`developed. This formulation demonstrated mycological and clinical
`efficacy in in vitro28 models of onychomycosis and was superior to
`ciclopirox 8% nail lacquer in a Phase II study.” This article presents
`results from three large clinical studies [two vehicle-controlled
`(2301 8t 2302) and one active comparator-controlled study
`(2303)] which assessed efficacy and safety of TNS used for 24
`weeks and 48 weeks in patients with mild-to-moderate toenail
`onychomycosis.
`
`Methods
`
`Study design
`
`controlled study, subjects received either TNS or amorolfine 5% nail
`
`lacquer for 48 weeks followed by a treatment free period of 4 weeks.
`The total duration of each study was 52 weeks. Subjects were
`randomized using a validated automated system in equal ratios.
`The studies were conducted in accordance with the ethical prin-
`ciples specified in the Declaration of Helsinki and in compliance
`with the requirements of local regulatory committees and all sub-
`jects provided written informed consent.
`
`Subjects
`
`Subjects aged 12-75 years with mild-to-moderate toe onychomy-
`cosis of the great toenail due to dermatophytes were included.
`Mild-to-moderate toe onychomycosis was defined as a toenail
`involvement of 225% to 575% without spikes and without matrix
`(lunula) involvement, and nail infection was confirmed by positive
`KOH microscopy and culture of a dermatophyte. The subjects
`who had nail abnormalities, obscuring appearance of infection-free
`normal nail (including traumatic or onychogryphotic nail) or in
`whom the target toenail had <2 mm unaffected nail plate length
`beyond the proximal fold were excluded. Also excluded were those
`
`with severe plantar tinea pedis requiring systemic therapy, mixed
`infections (dermatophyte and non-dermatophyte), der1natophy-
`toma (thick masses of fungal hyphae between the nail plate and
`nail bed),3° those receiving systemic or topical anti-fungal therapy
`within 6 months or 3 months, respectively, and those who used
`any commercial topical nail medication within 1 month. Subjects
`with severe diabetic foot neuropathy, malignancy, and sensitivity
`to the study medication were also excluded.
`
`Treatment
`
`Terbinafine nail solution or vehicle were supplied in identical
`packaging and were to be applied daily to all affected toenails with
`no surgical debridement, chemical avulsion, excessive grinding or
`filing of diseased nails. Amorolfine 5% nail lacquer was supplied
`as commercially available and was used as per label, twice weekly
`and with filling of the nails, as described in the package insert.
`
`Efficacy and safety assessments
`
`In the vehicle-controlled studies, subjects received either TNS or
`vehicle for 24 weeks or 48 weeks followed by a treatment free period
`of 28 weeks or 4 weeks respectively. In the active comparator-
`
`The primary efficacy measure was the proportion of subjects achiev-
`ing complete cure (no residual clinical involvement and negative
`KOH and culture) of the target toenail at week 52. The secondary
`
`IEADV 2013, 27, 287-294
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`to 2011 The Authors
`Journal of the European Academy of Dermatology and Venereology © 201 1 European Academy of Dermatology and Venereology
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`289
`Terbinafine nail solution for toenail onychomycosis
`
`
`efficacy endpoints were rates of mycological cure (negative KOH
`microscopy and negative culture for dermatophyte), clinical effec-
`tiveness (S10°/> residual involvement of the target toenail, negative
`culture and negative KOH microscopy) and clinical cure (no resid-
`ual involvement of the target toenail) at week 52. In addition, the
`proportion of subjects achieving a negative culture and 250%
`decrease in per cent involvement of the target toenail was analyzed.
`The safety assessments included monitoring and recording of all
`adverse events until week 52.
`
`Susceptibility testing
`
`Terbinafine susceptibility, expressed as minimum inhibitory con-
`centration (MIC) and minimum fungicidal concentration (MFC),
`for all strains isolated at baseline was assessed using the method
`
`developed under auspices of the Clinical and Laboratory Standards
`Institute (CLSI)."’32
`
`Statistical analyses
`Data from the two vehicle-controlled studies were combined for
`
`analysis. The intent-to-treat (ITT) population included all subjects
`who were randomized and