Pediatrics 2015 Sigurgeirsson Peds.2014 1990

Safety and Efcacy of Pimecrolimus inAtopic Dermatitis: A 5-YearRandomized TrialBardur Sigurgeirsson, MD, PhDa, Andrzej Boznanski, MD, PhDb, Gail Todd, FFDerm (SA), PhDc, Andr Vertruyen, MDd,Marie-Louise A. Schuttelaar, MD, PhDe, Xuejun Zhu, MDf, Uwe Schauer, MDg, Paul Qaqundah, MD, FAAP, FACAAIh,Yves Poulin, MD, FRCPCi, Sigurdur Kristjansson, MD, PhDj, Andrea von Berg, MDk, Antonio Nieto, MD, PhDl,Mark Boguniewicz, MDm, Amy S. Paller, MS, MDn, Rada Dakovic, PhDo, Johannes Ring, MD, PhDp, Thomas Luger, MDq

abstractBACKGROUND AND OBJECTIVES: Atopic dermatitis (AD) primarily affects infants and young children.Although topical corticosteroids (TCSs) are often prescribed, noncorticosteroid treatments areneeded because compliance with TCSs is poor due to concerns about their side effects. In thislongest and largest intervention study ever conducted in infants with mild-to-moderate AD,pimecrolimus 1% cream (PIM) was compared with TCSs.

METHODS: A total of 2418 infants were enrolled in this 5-year open-label study. Infants wererandomized to PIM (n = 1205; with short-term TCSs for disease ares) or TCSs (n = 1213). Theprimary objective was to compare safety; the secondary objective was to document PIMslong-term efcacy. Treatment success was dened as an Investigators Global Assessmentscore of 0 (clear) or 1 (almost clear).

RESULTS: Both PIM and TCSs had a rapid onset of action with .50% of patients achievingtreatment success by week 3. After 5 years,.85% and 95% of patients in each group achievedoverall and facial treatment success, respectively. The PIM group required substantially fewersteroid days than the TCS group (7 vs 178). The prole and frequency of adverse events wassimilar in the 2 groups; in both groups, there was no evidence for impairment of humoral orcellular immunity.

CONCLUSIONS: Long-term management of mild-to-moderate AD in infants with PIM or TCSs wassafe without any effect on the immune system. PIM was steroid-sparing. The data suggest PIMhad similar efcacy to TCS and support the use of PIM as a rst-line treatment of mild-to-moderate AD in infants and children.

WHATS KNOWN ON THIS SUBJECT: Topicalcorticosteroids are often used to treat atopicdermatitis (AD) in infants, although complianceis poor due to concerns over side effects.Pimecrolimus was shown to be a safe andeffective noncorticosteroid treatment of AD ininfants in short-term studies.

WHAT THIS STUDY ADDS: The Petite Study showsthat long-term management of mild-to-moderateAD in infants with pimecrolimus or topicalcorticosteroids was safe without any effect onthe developing immune system. Pimecrolimushad similar efcacy to topical corticosteroidsand a marked steroid-sparing effect.

aFaculty of Medicine, Department of Dermatology, University of Iceland, Reykjavik, Iceland; bDepartment ofChildren Allergology and Cardiology, Wroclaw Medical University, Wroclaw, Poland; cDepartment of Medicine,University of Cape Town, Cape Town, South Africa; dGZA Campus Sint-Vincentius, Antwerpen, Belgium; eDepartmentof Dermatology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands;fDepartment of Dermatology, Peking University First Hospital, Beijing, China; gKlinik fr Kinder undJugendmedizin, der Ruhruniversitt Bochum, Bochum, Germany; hPediatric Care Medical Group, HuntingtonBeach, California, and University of California, Irvine, California; iLaval University, Hpital Htel-Dieu de Qubec,Dermatology Unit and Centre de Recherche Dermatologique du Qubec Mtropolitain, Quebec City, Canada;jDepartment of Pediatrics, Landspitali-University Hospital, Reykjavik, Iceland; kResearch Institute, ChildrensDepartment, Marien-Hospital-Wesel, Wesel, Germany; lPediatric Pulmonology & Allergy Unit, Childrens Hospital LaFe, Valencia, Spain; mDivision of Pediatric Allergy-Immunology, Department of Pediatrics, National Jewish Healthand University of Colorado School of Medicine, Denver, Colorado; nDepartments of Dermatology and Pediatrics,Northwestern University Feinberg School of Medicine, Chicago, Illinois; oMeda Pharma GmbH & Co. KG, BadHomburg, Germany; pDepartment of Dermatology and Allergology Biederstein, Christine Khne-Center for AllergyResearch and Education, Technische Universitt Mnchen, Munich, Germany; and qDepartment of Dermatology,University of Mnster, Mnster, Germany

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Atopic dermatitis (AD) is a chronicinammatory, relapsing, and pruriticskin disease that affects up to 25% ofinfants and has a substantial impacton the quality of life of both patientsand their families.13 AD, togetherwith food allergy, is thought to be therst step of the atopic march, inwhich allergen exposure of the skincan lead to the subsequentdevelopment of asthma and allergicrhinoconjunctivitis.4 Patients with ADoften need frequent interventions fordisease ares and sometimes long-term continuous therapy to suppressthe inammation of the skin. Topicalcorticosteroids (TCSs) are commonlyused as rst-line treatment of AD,5

although their long-term safety andefcacy have not been investigated ininfants. More than 80% of patients orcaregivers have concerns aboutprescribed TCSs, and approximatelyone-third of AD patients arenoncompliant with TCSs because offactors such as their potential sideeffects,6 which highlights the need foralternative noncorticosteroidtreatments.

Pimecrolimus cream 1% (PIM) isa topical calcineurin inhibitor thatselectively suppresses activation ofT cells and mast cells.7,8 PIM is oftenrecommended by prescribers as rst-line AD therapy for sensitive skinareas because it causes neitherepidermal barrier functionimpairment nor skin atrophy.5,9,10 Upto 2 years of PIM is effective and welltolerated in infants and children withmild-to-moderate AD.1116 The PetiteStudy sought to compare the safetyand efcacy of PIM and TCSs for themanagement of mild-to-moderateinfantile AD during 5 years ofevaluation. The safety analysisincluded several assessments ofimmune function, given concerns thatPIM-mediated immunomodulationcould affect the developing immunesystem. The study used a unique real-world design in which TCSs wereused according to their label and inwhich the caregivers of infantsrandomized to treatment with PIM

had ready access to short-term TCSsas rescue medication if AD arescould not be controlled with PIM.

METHODS

Patient Population

Patients were enrolled into the studybetween April 2004 and October2005. Eligible infants were aged $3to ,12 months, and AD wasdiagnosed according to the criteria ofSeymour et al17 (because thesecriteria were developed for patientsaged #2 years) with disease affecting$5% of the total body surface area(TBSA). Patients had an InvestigatorsGlobal Assessment (IGA) score of 2 or3 (scale range: 05; SupplementalTable 3), indicating mild-to-moderatedisease.

Patients were excluded if they usedsystemic corticosteroids,immunosuppressants, cytostaticdrugs, or phototherapy within4 weeks of the rst application ofstudy medication, topical tacrolimusointment or PIM within 2 weeks, andtopical therapy for AD such as TCSswithin 3 days. Also excluded wereimmunocompromised patients andthose with a history of malignantdisease, active acute viral skininfection, or clinically infected AD.

Study Design

The primary objective of this 5-year,multicenter, open-label, randomized,parallel group study (www.clinicaltrials.gov identierNCT00120523) was to compare thesafety of PIM and TCSs over the rst 5to 6 years of life by assessing adverseevents (AEs), and the effects oftreatments on the developingimmune system and growth rate. Thesecondary objective was to examinethe long-term efcacy of PIM.

Patients were randomized in a 1:1ratio to either PIM 1% cream or TCS(low potency, eg, hydrocortisone 1%;or medium potency, eg,hydrocortisone butyrate 0.1%;cream/ointment used according to

the countrys label with potencyselected by the investigator), andrandomization was stratied bycenter and age group (36 and.6,12 months) using a validatedInteractive Voice Response System.Details of the treatment plan areshown in Supplemental Table 4.Study medication was startedimmediately after randomization andcontinued until complete ADclearance or for as long as allowed bythe label of the specic TCS.Medication was reinitiated at theoccurrence of rst signs andsymptoms of AD ares. Investigatorsexplained to caregivers of patients inboth groups what constituted diseaseworsening and, to those in the PIMgroup, when to stop PIM and startusing a TCS, that is, as a rescuemedication for an exacerbation notcontrolled by PIM.

The study was conducted inaccordance with Good ClinicalPractice and the Declaration ofHelsinki. The study protocol wasapproved by the Independent EthicsCommittee or Institutional ReviewBoard for each center. Caregiversprovided written informed consentfor infants participation in the study.

Efcacy and Safety Assessments

Efcacy was evaluated byinvestigators during clinic visits usingthe IGA (range 05) for the wholebody with a score of 0 (clear) or 1(almost clear) indicating treatmentsuccess, and the TBSA affected byinammation. Special considerationwas given to facial AD. Thesestraightforward and nontime-consuming efcacy assessments wereconsidered suitable for this large-scale clinical study.

All AEs were coded by system organclass and preferred term according tothe Medical Dictionary for RegulatoryActivities (version 13.1). (AEs ofprimary clinical interest as dened bythe US Food and Drug Administrationare identied in Fig 3 later in thearticle.) Growth rate was assessed bymeasuring height and weight at each

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visit. AEs recorded for the PIM groupmay have occurred either duringtreatment with PIM or with TCS fora are.

Immunology assessments includedantibody titers to common vaccineantigens, evaluations of humoral andcellular immune responses, and T-cellfunction tests (see SupplementalInformation).

Statistical Analysis

The safety and intent-to-treatpopulations included all randomizedpatients who received at least 1application of study medication.Assuming a 40% dropout rate,a sample size of 2350 infants wasconsidered to provide $80% or$90% power to determine whetherthe AE incidence rates under varyingscenarios were equivalent in thetreatment groups. This calculationassumed that the expected truedifference was zero and used theupper bound of the 97.5% condenceinterval as the upper equivalencelimit. The immunology testpopulation comprised all patientswho had at least 1 immune systemfunction assessment and was toinclude 350 patients per treatmentgroup. All signicance testing was2-sided at the 5% signicance level.

The primary safety analyses wereperformed on AEs of primary clinicalinterest and those with a crudeincidence of $5% in either treatmentgroup. These included Kaplan-Meieranalysis of time to rst occurrence ofthe AE. AE proles for the treatmentgroups were compared using the log-rank test. Additionally, AE counts inspecic time intervals were analyzedusing a Generalized EstimatingEquations Poisson regression modelwith baseline age and IGA, time, andtreatment as explanatory variables.The crude incidence rate and relativerisk based on the incidence densityrate were also calculated for the AEsof primary clinical interest. Theincidence density rate per 1000person-months was calculated as1000 3 total number of events / total

monitoring time in months (ie, sum ofstudy durations in months across allpatients in a treatment group).

The presence or absence of antibodytiters against vaccines was analyzedusing a logistic regression model withtime of vaccination, age group, andtreatment as explanatory variables.Treatment group differences inpercentage change from baseline toeach postbaseline time point in Tand B lymphocytes, andimmunoglobulins (Ig) were evaluatedtogether with 95% condenceintervals calculated under theassumption of equal variances usingpooled variance. Candida skin andT-cell function tests were reportedwith descriptive statistics.

Analysis of growth rate was done bycalculating the percentile and z scorefor height and weight for each patientat time points dened in the protocolusing standard growth curves for theUS population.18 The mean andchange from baseline for observed

height and weight as well aspercentiles were summarized bytreatment group at each time point.A mixed model analysis of the growthcurve data were also performed toexamine developmental trajectorieswith height and weight z scores as theresponse variable and time andtreatment as explanatory variables.

No statistical testing of efcacy endpoints was performed.

RESULTS

Patients

Overall, 2439 infants wererandomized into the study, 2418 ofwhom received at least 1 dose ofstudy drug (PIM, 1205; TCS, 1213)and were included in the efcacy andsafety evaluations. A similarproportion of patients in each groupcompleted the treatment period: PIM,69.4%; TCS, 72.1% (Fig 1). Thebaseline demographic and clinicalcharacteristics of the treatment

FIGURE 1Patient disposition.

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groups were similar (Table 1). Oninclusion, the majority of patientswere 6 to 12 months old. Althoughthe study was designed to enrollinfants aged $3 to ,12 months, 15patients older than 12 months (14patients ,12.5 months old; 1 patient12.8 months) were entered andincluded in the analyses. The 383PIM- and 391 TCS-treated patientsin the immunology test populationhad similar baseline characteristicsto the overall population (data notshown).

Efcacy

Both PIM and TCSs had a rapid onsetof action (Fig 2). More than 50% ofinfants in both groups achievedoverall (PIM, 52.6%; TCS, 50.5%) orfacial IGA (PIM, 61.0%; TCS, 61.8%)treatment success (ie, IGA #1) byweek 3. The median TBSA affected byAD decreased from 16% at baselineto ,5% by week 3 (PIM, 3.8%; TCS,

4.0%; Fig 2). At the end of the 5-yearstudy, .85% (PIM, 88.7%; TCS,92.3%) and 95% (PIM, 96.6%; TCS,97.2%) of patients achieved overalland facial IGA treatment success,respectively (Fig 2A and 2B).Similarly, the median TBSA affectedby AD decreased to 0% after 1.5 yearsof as-needed treatment and wasmaintained at this level for the rest ofthe study (Fig 2C).

TCS and Pimecrolimus Exposure

PIM was associated with a steroid-sparing effect. Thirty-six percent ofpatients in the PIM group did not useany TCSs. Overall, the patients in thePIM group used TCSs for a median ofonly 7 days (Q1: 0, Q3: 49 days)compared with 178 days (Q1: 77, Q3:396 days) in the TCS group over the5-year study period (SupplementalFig 5). Patients in the PIM group usedPIM for a median of 224.5 days (Q1:90, Q3: 452 days).

Safety

The frequency of the most commonAEs was similar in both treatmentgroups (Supplemental Table 5). Therewere few discontinuations due to AEs(PIM, 0.6% [most common:application site reactions, 3 patients];TCSs, 1.0% [most common:telangiectasia, 2 patients]). There wasno difference in growth rate betweenthe groups or in the Kaplan-Meieradjusted incidence of frequent AEs($5%) or AEs of primary clinicalinterest, such as bacterial or viralinfections. Analysis of event countsfor frequent AEs using the repeatedPoisson regression model showedthat patients in the PIM groupexperienced more AEs of bronchitis(P = .02), infected eczema (P , .001),impetigo (P = .045), andnasopharyngitis (P = .04). During therst 6 weeks and the entire study, thecrude incidence and incidencedensity rate for the AEs of primaryclinical interest were similar (Fig 3).There were no differences in theKaplan-Meier analysis of the time torst occurrence of these AEs.

Two deaths were reported in the TCSgroup, but considered unrelated tostudy medication (drowning, acutelymphocytic leukemia). The overallincidence of SAEs (PIM, 20.5%; TCS,17.3%) and serious infections andinfestations (13.0% vs 12.4%) weresimilar in the 2 groups. Twomalignancies occurred in the TCSgroup (acute lymphocytic leukemia,ependymoma), and 1 benign tumorwas reported in the PIM group(pilomatrixoma).

Immune System

Infants treated with PIM or TCSsdeveloped similar and normalantibody titers to common vaccineantigens (Table 2). To evaluate themagnitude of the antibody response ofinfants being treated with study drugafter immunization, the response toHaemophilus inuenza type b vaccinewas assessed by measuring antibodytiters before the third dose of primaryvaccination and 30 days

TABLE 1 Patient Baseline Demographic and Disease Characteristics

PIM 1% (n = 1205) TCS (n = 1213)

Age, moMean (SD) 7.1 (2.7) 7.1 (2.7),3, n (%) 4 (0.3) 7 (0.6)36, n (%) 500 (41.5) 485 (40.0).6,12, n (%) 694 (57.6) 713 (58.8)$12, n (%) 7 (0.6) 8 (0.7)

Gender, n (%)Male 744 (61.7) 742 (61.2)

Race, n (%)Caucasian 736 (61.1) 713 (58.8)Black 66 (5.5) 80 (6.6)Asian 119 (9.9) 118 (9.7)Other 284 (23.6) 302 (24.9)

TBSA affectedMean (SD) 21.1 (16.5) 21.3 (17.2),15%, n (%) 568 (47.1) 575 (47.4)15,30%, n (%) 378 (31.4) 367 (30.3)$30%, n (%) 259 (21.5) 271 (22.3)

IGA, n (%)2, Mild disease 570 (47.3) 558 (46.0)3, Moderate disease 635 (52.7) 652 (53.8)4, Severe disease 0 2 (0.2)5, Very severe disease 0 1 (0.1)

Facial IGA, n (%)0, Clear 71 (5.9) 74 (6.1)1, Almost clear 88 (7.3) 84 (6.9)2, Mild disease 497 (41.2) 501 (41.3)3, Moderate disease 541 (44.9) 537 (44.3)4, Severe disease 7 (0.6) 15 (1.2)5, Very severe disease 1 (0.1) 1 (0.1)Not stated 0 1 (0.1)


postimmunization in a subset ofpatients. In both groups, all patientsbut 1 were seropositive (Table 2).

The increase in Ig levels and thedecrease in peripheral blood T andB lymphocytes from baseline to week

260 were similar in both groups(Fig 4, Supplemental Fig 6) andconsidered normal compared withhistorical controls (for example, seeSupplemental Fig 7). The proportionof patients with positive Candida skintests was similar between treatmentgroups (baseline: PIM, 14.0%; TCS,9.2%; week 260: 15.3% vs 14.3%).T-cell function was assessed by ex vivocytokine production in response tostimulation with anti-CD3 antibodiesand tetanus antigen. Accordingly, theproduction of interleukin (IL)-2, IL-4,IL-10, and interferon-g wascomparable in the 2 treatment groups,indicating a similar nonantigenspecic activation response andspecic antigen response(Supplemental Fig 8).

DISCUSSION

We investigated the safety andefcacy of PIM and TCSs in the largestpopulation of infants with AD and forthe longest time period (ie, the rst56 years of life) ever studied. Infantsaged $3 to ,12 months wereselected for inclusion so that theeffects of treatment could beinvestigated from early infancythrough early childhood. The efcacyresults suggest that PIM has similarefcacy to TCSs in a real-worldsetting, which is noteworthy becausePIM is not currently widely used asrst-line therapy for AD, given theperception of lower efcacy thanTCSs.19 Both treatments had a rapidonset of action (within 3 weeks).After 5 years of as-needed treatment,88.7% PIM-treated and 92.3% TCS-treated infants had only minimaldisease, which could reecta progressive increase in treatmentefcacy and/or the naturalprogression of AD, which tends to getmilder as children get older. The rapidand continuous improvement in ADmay decrease the substantial physicaland emotional burden caused by thisdistressing skin condition.20 Thesendings conrm and extend thosefrom previous shorter studies ininfants and young children, which

FIGURE 2Long-term efcacy of PIM compared with TCSs: A, overall; B, facial IGA treatment success (IGA #1); C,TBSA affected. IGA treatment success is dened as an IGA score of 0 (clear) or 1 (almost clear).


showed that PIM leads to rapid reliefof pruritus, prevention of progressionto major ares, and increases in thenumber of disease-free days.11,12,21,22

Treatment with PIM resulted ina substantial corticosteroid-sparingeffect, with 36% of children notrequiring any TCSs over the 5-year

study. Patients in the PIM groupused TCSs for a median of only 7days. The markedly decreased needfor TCSs is important because it

FIGURE 3Crude incidence and relative risk for AEs of primary clinical interest during (A) 6 weeks and (B) entire treatment period. Incidence density ratio wascalculated as 1000 3 total number of events / total monitoring time in months. CI, condence interval.


indicates that AD patients can beeffectively treated witha noncorticosteroid alternative. Up toone-third of patients are not compliantwith TCS treatment because ofcorticophobia, resulting from factorssuch as fear of their potential sideeffects.6,2325 The steroid-sparingeffect of PIM may help to improve

treatment compliance, although thiswas not specically assessed in thePetite Study.

In this 5-year study, there were nosafety concerns with real-life use ofPIM or TCSs. Overall, the type andfrequency of AEs including infectionswere as expected for this patientpopulation.26,27 There were no cases of

T-cell lymphoma or skin malignancieswith PIM during the study, inagreement with the ndings of severallong-term epidemiologic studies.28,29

There was an overall trend towardPIM being associated with a lowerrisk of rhinorrhea, wheezing, viralrash and lower respiratory tractinfection over the entire treatmentperiod (Fig 3). However, theincidence of some mild infections(bronchitis, impetigo,nasopharyngitis, infected eczema)was signicantly higher with PIMthan with TCSs. In contrast,a randomized double-blind study inadults reported a higher incidence ofinfections with TCSs.30 Thedifferences in AE incidence betweengroups were only 2% to 4%, and theanalyses were not adjusted for themultiplicity of comparisons.

TABLE 2 Patients With Positive Antibody Titresa

Vaccine PIM 1% (n = 383) TCS (n = 391) OR (95% CI)

n/N (%) n/N (%)

Tetanus 164/180 (91.1) 169/190 (88.9) 0.8 (0.51.2)Hepatitis B 63/182 (34.6) 73/191 (38.2) 1.2 (0.91.6)Measles 180/182 (98.9) 181/188 (96.3) 0.8 (0.51.2)Varicellab 27/31 (87.1) 37/44 (84.1) 2.2 (1.04.7)Hibc 26/27 (96.3) 30/31 (96.8) 0.9 (0.114.6)

CI, condence interval; Hib, Haemophilus inuenza type b; n/N, number of patients with positive antibody titers / totalnumber of patients with antibody titer measurements; OR, odds ratio.a At week 260 for tetanus, hepatitis B, measles, varicella; 30 d postimmunization and before third dose for HIB.b Only assessed for patients from the United States (PIM 1%, n = 104; TCS, n = 108).c Only assessed in subset of patients from the United States and Canada.

FIGURE 4Ig levels over time: A, IgA; B, IgE; C, IgG; and D, IgM.


Therefore, the clinical signicance ofthe observed small differences in theincidence of 4 specic AEs needs tobe interpreted with caution.

The immunologic investigations inthis study represent the mostcomprehensive assessment everperformed of the impact of real-lifeAD treatment on the maturation ofthe immune system in a largeinternational population of infantswith AD during the rst 5 to 6 yearsof life. Our study did not includea placebo arm for ethical reasons;however, the increase in Ig levels anddecrease in circulating T andB lymphocytes were similar in bothgroups and consistent with thenormal maturation of the systemicimmune system in healthychildren.3136 Previous studies haveshown that IgG and IgA levelsprogressively rise during the rstyears of life in healthy children. IgEalso rises, but to a lesser extent, andthe levels of IgM plateau before thoseof the other Ig categories, inagreement with our ndings.3134

Also similar to our observations,other studies have demonstrated thatT and B lymphocyte counts peak in

the rst 1 to 2 years of life, followedby a slow decline to adult levels overtime.35,36 The postvaccinationantibody titers showed that mostpatients developed a normal immuneresponse to childhood vaccinations,and the response was similar in the 2treatment groups. The currentimmunologic data conrm previousinvestigations demonstrating that upto 2 years of PIM treatment in infantsdid not result in an increased rate ofsystemic or skin infections anddevelopment of immune responsesafter vaccination werenormal.11,12,16,21,37 These resultsprovide important real-world datasupporting the safety of PIM ininfants and young children witha developing immune system. Thelack of systemic immunosuppressionis likely due to the minimal systemicdrug exposure in both infants andchildren.38,39

CONCLUSIONS

The Petite Study begins to addressrecommendations from regulatoryagencies and The TopicalCalcineurin Inhibitor Task Force ofthe American College of Allergy,

Asthma and Immunology that morestudies are needed to addressquestions about the efcacy andsafety of topical immunosuppressivemedications specically in pediatricpopulations with AD.40 The resultsof the Petite Study show for the rsttime that as-needed rst-linetreatment with PIM or TCSs has nosafety concerns and no impact onthe maturation of the developingimmune system. The data suggestthat PIM had similar efcacy to TCSand PIM was associated witha substantial corticosteroid-sparingeffect. The study provides real-worlddata for the use of PIM as a rst-linetreatment of mild-to-moderate AD ininfants and children.

ACKNOWLEDGMENTS

We thank all of the investigatorsinvolved in the Petite Study (seeSupplemental Information) as well asthe children and their caregivers whoparticipated in this study. We alsothank David Harrison, MedscriptCommunications, for providingeditorial assistance which was fundedby Meda Pharma GmbH & Co. KG(Bad Homburg).

Dr Sigurgeirsson was the principal investigator for this study and as such approved the study report and vouches for the data; he contributed to the design and

conduct of the study, collection of data, analysis and interpretation of the results, writing and critical review of the manuscript; Drs Boznanski, Todd, Schuttelaar,

Zhu, Qaqundah, Kristjansson contributed to the acquisition of data for the study and critically reviewed the manuscript; Drs Vertruyen, Schauer contributed to the

acquisition of data for the study and drafting the manuscript and critically revising its content; Drs Poulin and Nieto contributed to the acquisition of data for the

study, analyzed and interpreted the results, and critically revised the manuscript; Dr von Berg contributed to the acquisition of data for the study, was involved in

the interpretation of the results, and critically revised the manuscript; Dr Boguniewicz contributed to acquisition of data for the study and provided critical input

into the initial and revised manuscript; Dr Paller carried out the initial analyses, reviewed and revised the manuscript; Dr Dakovic contributed to the analysis of

data and critically reviewed the manuscript; Drs Ring and Luger analyzed and interpreted the results and reviewed and revised the manuscript; and all authors

approved the nal manuscript as submitted.

This trial has been registered at www.clinicaltrials.gov (identier NCT00120523).

www.pediatrics.org/cgi/doi/10.1542/peds.2014-1990

DOI: 10.1542/peds.2014-1990

Accepted for publication Jan 5, 2015

Address correspondence to Bardur Sigurgeirsson, MD, PhD, Hudlaeknastodin, Smaratorg 1, 201 Kopavogur, Iceland. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2015 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr Paller has consulted for Valeant. The other authors have no nancial relationships relevant to this article to disclose.

FUNDING: Supported by Novartis Pharmaceuticals Corporation. Editorial assistance in the preparation of this manuscript was funded by Meda Pharma GmbH & Co. KG.

POTENTIAL CONFLICTS OF INTEREST: Dr Sigurgeirsson has received research grants from or lectured/consulted for Novartis, Galderma, Amgen, Topica, Viamet,

Prostrakan, and Stiefel. Dr Bozanski has been an investigator for Novartis. Dr Schuttelaar has been an investigator for Novartis and Astellas. Dr Poulin has received


research grants from Astellas and Novartis. Dr Nieto has been an advisor for Novartis and Meda and has participated in meetings sponsored by Novartis and Meda.

Dr Paller has been an investigator for Astellas and a consultant with honorarium for Valeant. Dr Dakovic is an employee of Meda. Dr Ring has received research

grants from or lectured/consulted for Astellas, Meda, and Novartis. Dr Luger has collaborated, advised, and lectured for Astellas, Meda, and Novartis. The other

authors have indicated they have no potential conicts of interest to disclose.

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DOI: 10.1542/peds.2014-1990; originally published online March 23, 2015;Pediatrics

Rada Dakovic, Johannes Ring and Thomas LugerKristjansson, Andrea von Berg, Antonio Nieto, Mark Boguniewicz, Amy S. Paller,A. Schuttelaar, Xuejun Zhu, Uwe Schauer, Paul Qaqundah, Yves Poulin, Sigurdur

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Safety and Efficacy of Pimecrolimus in Atopic Dermatitis: A 5-Year Randomized

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Rada Dakovic, Johannes Ring and Thomas LugerKristjansson, Andrea von Berg, Antonio Nieto, Mark Boguniewicz, Amy S. Paller,A. Schuttelaar, Xuejun Zhu, Uwe Schauer, Paul Qaqundah, Yves Poulin, Sigurdur

Bardur Sigurgeirsson, Andrzej Boznanski, Gail Todd, Andr Vertruyen, Marie-LouiseTrial

Safety and Efficacy of Pimecrolimus in Atopic Dermatitis: A 5-Year Randomized

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