l s

. D

NorthEast Medical Research Associates, North DarxGlaxoSmithKline, Research Triangle Park, North CajjHarvard Medical School, Boston, Massachusetts{Chylack Inc, Duxbury, Massachusetts

A R T I C L E I N F O

Article history:Received for publication October 31, 2012.Received in revised form April 6, 2013.Accepted for publication April 16, 2013.

Fluticasone furoate nasal spray (FFNS) (Veramyst Nasal Spray;GlaxoSmithKline, Research Triangle Park, North Carolina) is an

use of FFNS, 110 mg once daily, in adult and adolescent patients withPAR. To date, it is the rst randomized, double-blind, placebo-controlled, parallel-group study, to our knowledge, to evaluate the

Contents lists available at

Ann Allergy Asthma Immunol 111 (2013) 45e50most common drug-related adverse event was epistaxis (FFNS, 28%; placebo, 14%).Conclusion: These data neither support nor negate current recommendations for regular ophthalmicmonitoring in patients treated with intranasal corticosteroids.Trial Registration: clinicaltrials.gov Identier: NCT00682643. 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction

The chronicity of perennial allergic rhinitis (PAR) often necessi-tates long-term pharmacologic therapy. However, there is a paucityof data describing the benets and risks of long-term use of intra-nasal corticosteroids. Clinical studies lasting up to 1 year with intra-nasal corticosteroids demonstrated a favorable benet-risk prole.1,2

intranasal corticosteroid approved by the Food and Drug Admin-istration (FDA) for the symptoms of allergic rhinitis.3 The potentialfor adverse effects on the eyes (eg, cataracts and glaucoma) is notedas a potential class effect in the prescribing information of allintranasal corticosteroids.

This report describes the results of a 2-year postmarketing studywhose objective was to evaluate the ocular effects of continuousRo(PIITReprints: Laurie A. Lee, MD, GlaxoSmithKline, 5 MNC 27709; E-mail: laurie.a.lee@gsk.com.Disclosures: Drs Wu and Lee are current GlaxoSwas employed by GlaxoSmithKline during the coDr Chylack was a consultant to GlaxoSmithKlinOpacities Classication System training and cerLaForce, Journeay, and Miller were study investioSmithKline for this study.Funding Sources: This study was funded bFFR110537).

1081-1206/13/$36.00 - see front matter 2013 Ahttp://dx.doi.org/10.1016/j.anai.2013.04.013tmouth, Massachusettsrolina

A B S T R A C T

Background: This is the rst study, to our knowledge, to evaluate the ocular effects of an intranasal corti-costeroid during 2 years of treatment for perennial allergic rhinitis (PAR).Objective: To assess ocular safety in adult and adolescent patients 12 years and older with PAR after 2 yearsof continuous treatment with uticasone furoate nasal spray (FFNS), 110 mg once daily, and placebo.Methods: This was a 2-year, randomized, double-blind, placebo-controlled study of once-daily FFNS, 110 g,and placebo in 548 patients 12 years and older with PAR. The primary ocular safety end points were time torst occurrence of an event for the Lens Opacities Classication System, Version III (LOCS III), posteriorsubcapsular opacity (PSO) and time to rst occurrence of an event for intraocular pressure (IOP).esults: On the basis of survival analyses, the difference between the treatment groups for time to rstccurrence of a LOCS III PSO and time to rst occurrence of an IOP event was not statistically signicant .39 and P .34, respectively). Changes from baseline in visual acuity, LOCS III PSO, cortical opacity, LOCS

I nuclear opacity and nuclear color, IOP, and horizontal cup-to-disc similar between treatment groups.here were no ophthalmic-related adverse events of LOCS III PSO or IOP that led to early withdrawal. The*North Carolina Clinical Research, Raleigh, North CaroyAustin Clinical Research Inc, Austin, TexaszlinaWei Wu, PhD ; Laurie A. Lee, MD ; and Leo T. Chylack, Jr, MDOcular safety of uticasone furoate nasarhinitis: a 2-year studyCraig LaForce, MD *; Glen E. Journeay, MD, PhD y; S

x xoore Dr, Research Triangle Park,

mithKline employees. Ms Silveynduct and analysis of the study.e and responsible for the Lenstication during the study. Drsgators and consultants for Glax-

y GlaxoSmithKline (GSK study

merican College of Allergy, Asthma &pray in patients with perennial allergic

avid Miller, MD z; Mary Jane Silvey, MBA x;jj,{

SciVerse ScienceDirectlong-term safety of the continuous use of an intranasal cortico-steroid during a 2-year period in which adherence was monitoredby daily diary and video-phone observations and in which regularophthalmologic evaluations were performed by ophthalmologiststrained and certied in the Lens Opacities Classication System,Version III (LOCS III). LOCS III is a widely used method of subjec-tively grading the type and severity of lens opacities by comparinga patients lens opacities to a set of standard photographs that

Immunology. Published by Elsevier Inc. All rights reserved.

sthmillustrate differing degrees of nuclear (including nuclear opacity[NO] and nuclear color [NC]), cortical (C), and posterior subcapsularopacities (PSO) formation.4e6 The design and duration of the studyand the use of LOCS III were discussed and agreed on by the studysponsor and the FDA before the start of the study.

Methods

Study Design and Treatment

This study (GlaxoSmithKline protocol FFR110537; ClinicalTrials.gov identier NCT00682643 was conducted at 53 centersin the United States in compliance with Good Clinical Practice andthe Declaration of Helsinki (2008) and was approved by all relevantinstitutional review boards. The study was initiated on June 30,2008, and completed on February 18, 2011. Following a 7- to 14-dayscreening period, eligible patients were randomized in a 2:1 ratio(FFNS, 110 mg once daily:placebo) to FFNS, 110 mg once daily, andplacebo nasal spray. A total of 525 randomized patients (350 toFFNS 110 mg and 175 to placebo) was planned at approximately 40to 70 investigational sites. The randomization was stratied by age(12 to

or study (n=804)

Screen failures excluded (n=254)

Placebo (n=181)

Completed study (n=104)Prematurely withdrew (n=77)

-Adverse event (n=12)-Lack of efficacy (n=2)-Protocol deviation (n=38)-Reached protocol defined stopping criteria

ized (n=550)

ted (n=448)

sthma Immunol 111 (2013) 45e50 47Screened f

FFNS 110mcg QD (n=367)

Completed study (n=199)Prematurely withdrew (n=168)

-Adverse event (n=23)-Protocol deviation (n=76)-Reached protocol-defining stopping criteria (n=4)-Investigator discretion (n=6)-Withdrew consent (n=53)-Lost to follow up (n=6)

Random

Trea

C. LaForce et al. / Ann Allergy AHispanic/Latino, or white. Baselinemean rTNSSswere 8.23 and 8.27(evaluated using a 12-point scale) in the FFNS and placebo groups,respectively, indicating that patients in both treatment groups hadPAR of moderate severity (Table 1). Mean exposure to treatmentwas 523.9 days in the FFNS group and 542.0 days in the placebogroup. Median exposure was 725.0 days in both groups.

Primary Ophthalmic End Points

Time to First Occurrence of an Event for LOCS III PSOThe difference between the treatment groups for time to rst

occurrence of an event for LOCS III PSO based on the survivalanalysis was not statistically signicant (P .40) (Table 2). Four-teen patients (4%) in the FFNS group and 4 patients (2%) in theplacebo group had an event for LOCS III PSO. Of the 14 patients inthe FFNS group who had a LOCS III PSO event, 10 patientscompleted the study. One FFNS patient had an event for PSO atweeks 36 and 64; these increases were observed during theremainder of the treatment period. Another FFNS patient had anevent for PSO at weeks 36, 64, 76, and 88; at weeks 52 and 104 theP values were equal to baseline. Two additional FFNS patients hadan event for PSO on 2 occasions during the treatment period; forboth patients, values were equal to baseline or0.2 of the baselinevalue on subsequent visit(s), including end of treatment or earlywithdrawal. In addition, 2 FFNS patients experienced an event forPSO at the end of their study treatment with no subsequentmeasurements. The remaining 8 patients in the FFNS group whohad an event for PSO experienced the event on one occasion onlyafter which their values were within 0.2 of baseline value for theremaining on-treatment assessments.

One patient in the placebo group had an event for PSO at weeks36, 52, 76, and 88. Another patient had an event for PSO on 2occasions, weeks 52 and 64, in both eyes; the values were equal to

Figure 1. Flow and disposition of patients throughout stud(n=3)-Investigator discretion (n=2)-Withdrew consent (n=19)baseline on subsequent visits. The 2 remaining patients in theplacebo group who had an event for PSO experienced this event onone occasion only.

y. Abbreviation: FFNS, uticasone furoate nasal spray.

Table 1Patient demographics and baseline dataa

Variable FFNS, 110 mg daily(n 367)

Placebo(n 181)

Age, mean (range), y 37.0 (12-70) 38.0 (12-65)Age group, y12 to

Table 2Analysis of time to rst occurrence of LOCS III PSO (intent-to-treat population)

Time to First PSO FFNS, 110 mg daily(n 367)

Placebo(n 181)

Postbaseline ophthalmic data, No. 344 168Censored patients, No. (%) 353 (96) 177 (98)Uncensored patients (events), No. (%) 14 (4) 4 (2)Cumulative percentage with eventa

Week 12 0.88 0.60Week 24 1.84 1.24Week 36 2.56 1.93Week 52 3.72 2.68Week 64 3.72 2.68Week 76 3.72 2.68Week 88 4.59 2.68Week 104 5.09 2.68

P value vs placebob .40

Abbreviations: FFNS, uticasone furoate nasal spray; LOCS III, Lens Opacities

C. LaForce et al. / Ann Allergy Asthm48Time to First Occurrence of an Event for IOPOn the basis of survival analysis, the difference between the

treatment groups for time to rst occurrence of an IOP event wasnot statistically signicant (P .34) (Table 3). Seven patients (2%) inthe FFNS group and 1 patient (99)Uncensored patients (events), No. (%) 7 (2) 1 (95%) in both treatment groupshad LOCS III PSO values that were within 0.1 of baseline for eacheye.

Change From Baseline in LOCS III C, NO, and NCChanges from baseline in LOCS III C, NO, and NC were small and

similar in both treatment groups during the entire treatmentperiod (mean change from baseline for both eyes rangedfrom 0.01 to 0.13 for FFNS and 0.00 to 0.24 for placebo).

Change From Baseline in IOPThe change from baseline in IOP during the visits was small and

similar in both treatment groups. Mean change from baseline forboth eyes ranged from 0.9 to 0.3 for FFNS and 1.0 to 0.3 forplacebo. The maximum increase in IOP during the 2-year treatmentperiodwas 8mmHg (one patient in each treatment group). The IOPreturned to within 2 mm Hg from baseline measurements for bothof these 2 patients at week 104. At weeks 52 and 104, most patients(>95%) had IOP values of within5mmHg of the baseline value. Inmore than 99% of the data, the difference between 2 eyes for eachpatient was within normal variability. There were 2 patients whohad deviations of 6 mm Hg between eyes at one study visit, yet theIOP remained within 1 mm Hg of the baseline value and neitherpatient had an event during the study.

Change From Baseline in logMAR Visual AcuityAt weeks 52 and 104, more than 70% of patients had logMAR

visual acuity values within 0.1 of baseline for each eye in bothtreatment groups. At week 52, no patient had changes in baseline of0.3 or higher in logMAR visual acuity values in either eye. At week104, 3 patients (2 in the FFNS group and 1 in the placebo group) hadchanges from baseline of 0.3 or higher in logMAR visual acuity.None of these patients had an event in LOCS III PSO or IOP.

Change From Baseline in Horizontal Cup-to-Disc RatioVery small mean changes or no change from baseline were

observed in horizontal cup-to-disc ratio in either treatment group(mean change from baseline range for both eyes was 0.0 to 0.7 forFFNS and 0.0 for placebo).

Other Safety Measures

Patients Who Met Ophthalmic Examination Early WithdrawalCriteria

Fifteen patients met ophthalmic examination early withdrawalcriteria (10 patients [3%] in the FFNS group and 5 [3%] in the placebogroup). Of these, 7 patients (4 in the FFNS group and 3 in theplacebo group) were identied and withdrawn for an ophthalmic-related adverse event. There were no events of LOCS III PSO or IOPthat led to early withdrawal.

Adverse EventsAdverse events were reported for 82% of the patients in each

treatment group. The most common adverse event was epistaxis(FFNS, 34%; placebo, 19%). Nasal ulcer and nasal septum ulcerationadverse events were reported in a higher proportion of patients inthe FFNS group (8% and 7%, respectively) compared with theplacebo group (2% and 3%, respectively).

The overall incidence of adverse events considered to be relatedto study medication by the investigator was 34% in the FFNS groupand 23% in the placebo group. The most common drug-related

a Immunol 111 (2013) 45e50adverse event reported was epistaxis (FFNS, 28%; placebo, 14%).The other commonly reported drug-related adverse events werenasal ulcer (FFNS, 7%; placebo, 1%) and nasal septum ulceration(FFNS, 5%; placebo, 3%) followed by nasal discomfort (FFNS, 3%;

placebo, 2%). The remaining drug-related adverse events occurredin less than 1% of patients across the treatment groups. One patientin the placebo group had a nasal septal perforation that wasconsidered to be drug related by the investigator.

Adverse events that led to early withdrawal were reported in 23patients (6%) in the FFNS group and 12 patients (7%) in the placebogroup. Nonfatal serious adverse events (none thought to be drugrelated) were reported in 12 patients (3%) in the FFNS group and 7(4%) in the placebo group. There were no cataract- or glaucoma-related adverse events observed during the study.

Clinical Laboratory Tests, Vital Signs, and Nasal ExaminationsNo notable changes were found from baseline in clinical labo-

ratory variables and vital signs in either treatment group. Mostpatients (87%) had no changes from baseline in mucosal bleeding,ulcers turbinates or septum, and polyposis turbinates or septumthroughout the study. The proportion of patients who had wors-ening in mucosal bleeding and ulcerated turbinates was higher in

No signicant difference was found in the time to rst event forPSO and IOP between the FFNS and placebo groups. However, theevents for PSO and IOP were more frequent in the FFNS groupcompared with the placebo group. There were no changes, or verysmall changes, in LOCS III PSO from baseline throughout the study.The maximum increases in LOCS III PSO during the 2-year treat-ment period were 1.0 in the FFNS group and 0.9 in the placebogroup, conrming that there were no events (2.0 increase in PSO)that required early withdrawal of patients. Of signicance is thending that more than 95% of patients in both treatment groupshad 1 and 2 year LOCS III PSO values that were within 0.1 ofbaseline. These data indicate the lack of any adverse effect of FFNSon the status of the posterior subcapsular region of the lens. Manypatients had increases in LOCS III PSO of 0.3 or greater that were notsustained (absent or 0.3 at later visits). Such increases werepossibly due to methodologic noise and not a true biologic devel-opment because cataract progression (age related and drug related)is almost always unidirectional (it only gets worse); retrogression

C. LaForce et al. / Ann Allergy Asthma Immunol 111 (2013) 45e50 49the FFNS group than in the placebo group.

Adherence to Treatment

Mean treatment adherence from weeks 1 to 104 based on thepatient diary and video-phone observationswas high (93% and 88%,respectively). Adherence based on nasal device weight also sup-ported patient adherence because mean daily use of nasal spraywas similar between the treatment groups. The efcacy data wereused as a measure for treatment adherence. At baseline, the meandaily rTNSS was similar for both treatment groups (FFNS, 8.2;placebo, 8.4). The mean difference from baseline (FFNS minusplacebo)was greater for the FFNS group comparedwith the placebogroup throughout the study (Fig 2). The least squares meandifference between the 2 treatments was 0.774 for weeks 1 to 4,greater than 1.0 fromweeks 5 to 8 onward, and 1.153 for the entiretreatment period (95% condence interval, 1.59 to 0.72).

Discussion

The results from this study demonstrated that continuoustreatment with FFNS for 2 years in patients with PAR did notadversely affect ocular safety as measured by monitoring of lensopacication (with LOCS III), IOP, visual acuity, and funduscopichorizontal cup-to-disc ratio. The events of PSO and IOP were notaccompanied by evidence of clinical disease, and there were nocataract- or glaucoma-related adverse events during the study.Figure 2. Mean change from baseline in daily reective total nasal symptom scores (rTNSof the cataract severity is biologically implausible.7 The choice ofthe LOCS III method of classifying lens opacicationwas reasonablefor a study inwhich therewas a need to document newly appearingopacication and acceleration of the naturally slow progression ofage-related cataract formation. LOCS II and III have been used inmany similar studies in the past 2 decades.7e9

Changes from baseline in IOP throughout the study were small.The maximum increase in IOP was 8 mmHg in either group. An IOPbetween 10 and 21 mm Hg is generally considered within normallimits; however, during a 24-hour period it can vary by 5 mm Hgbecause of normal diurnal variation.10 IOP events of an increase of7 mm Hg or greater in both treatment groups were transient and,therefore, of uncertain clinical signicance. As with events for PSO,a relationship to study treatment for IOP events seems unlikelybecause the patients exposure increased, yet the ocular ndingsoften did not persist.

The clinical implications of these data regarding patient care areunknown. Current recommendations for patients using intranasalcorticosteroids warn that patients with a change in vision or witha history of increased IOP, glaucoma, or cataracts should be moni-tored closely.

The strengths of this study included the following: (1) a well-dened and well-balanced population of treated and placebopatients; (2) a relatively long period of observation with patientsmanifesting excellent adherence to drug use schedules; (3)balanced dropout rates; (4) a validated and appropriate system forSs) (intent-to-treat population). Abbreviation: FFNS, uticasone furoate nasal spray.

classifying changes in the lens (LOCS III) used by physicians whowere uniformly trained, certied, and periodically recertied in theuse of the LOCS III system; (5) rigorous standardization of theexamination and lens classication procedures; and (6) conrma-tion of the validity of the LOCS III system in detecting the expectedage-related increases in NO, NC, C, and PSO.

In conclusion, survival analyses conducted after 2 years oftreatment in patients with PAR did not reveal signicant differencesbetween FFNS and placebo in time to occurrence of ocular eventsfor PSOs and increased IOP. The data neither support nor negatecurrent recommendations for regular ophthalmic monitoring inpatients treated with intranasal corticosteroids.

Acknowledgments

The authors wish to acknowledge the following individuals fortheir contributions and critical review during the development ofthe manuscript on behalf of GlaxoSmithKline: Kim Poinsett-Holmes, PharmD, of Poinsett Publications Inc for medical writingand editorial assistance; Laura Sutton, PharmD (GlaxoSmithKline),for editorial assistance; and the study investigators andparticipants.

References

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[3] Veramyst (uticasone furoate) Nasal Spray [prescribing information].Research Triangle Park, NC: GlaxoSmithKline; August 2011.

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[6] Chylack LT Jr, Wolfe JK, Singer DM, et al. The Longitudinal Study of CataractStudy Group. The Lens Opacities Classication System III. Arch Ophthalmol.1993;111:831e836.

[7] Leske MC, Wu SY, Nemesure B, Li X, Hennis A, Connell AM. Incidence andprogression of lens opacities in the Barbados Eye Studies. Ophthalmology.2000;107:1267e1273.

[8] Lim LS, Husain R, Gazzard G, Seah SK, Aung T. Cataract progression afterprophylactic laser peripheral iridotomy: potential implications for theprevention of glaucoma blindness. Ophthalmology. 2005;112:1355e1359.

[9] Husain R, Tong L, Fong A, et al. Prevalence of cataract in rural Indonesia.Ophthalmology. 2005;112:1255e1262.

[10] Bross-Soriano D, Hanenberg-Milver C, Schimelmitz-Idi J, Arrieta-Gomez JR,Astorga del Toro R, Bravo-Escobar G. Effects of three nasal topical steroids inthe intraocular pressure compartment. Otolaryngol Head Neck Surg. 2004;130:187e191.

C. LaForce et al. / Ann Allergy Asthma Immunol 111 (2013) 45e5050

Ocular safety of fluticasone furoate nasal spray in patients with perennial allergic rhinitis: a 2-year studyIntroductionMethodsStudy Design and TreatmentPatientsProceduresOphthalmic Examination Discontinuation CriteriaStudy AssessmentsStatistical Analyses

ResultsPatient Demographics and Baseline CharacteristicsPrimary Ophthalmic End PointsTime to First Occurrence of an Event for LOCS III PSOTime to First Occurrence of an Event for IOP

Secondary Ophthalmic End PointsChange From Baseline in LOCS III PSOChange From Baseline in LOCS III C, NO, and NCChange From Baseline in IOPChange From Baseline in logMAR Visual AcuityChange From Baseline in Horizontal Cup-to-Disc Ratio

Other Safety MeasuresPatients Who Met Ophthalmic Examination Early Withdrawal CriteriaAdverse EventsClinical Laboratory Tests, Vital Signs, and Nasal Examinations

Adherence to Treatment

DiscussionAcknowledgmentsReferences