Rhinitis, sinusitis, and upper airway disease

Mometasone furoate nasal spray reduces the ocularsymptoms of seasonal allergic rhinitis

Bruce M. Prenner, MD,a Bobby Q. Lanier, MD,b David I. Bernstein, MD,c Tulin Shekar, MS,d and Ariel Teper, MDd

San Diego, Calif, Fort Worth, Tex, Cincinnati, Ohio, and Kenilworth, NJ

Background: Mometasone furoate nasal spray (MFNS), apotent intranasal corticosteroid with proved efficacy in relievingnasal allergic rhinitis symptoms, has demonstrated effectivenessin improving ocular symptoms associated with seasonal allergicrhinitis (SAR) in retrospective analyses.Objective: We sought to evaluate prospectively the efficacy ofMFNS in reducing total ocular symptom scores (TOSSs) andindividual ocular symptoms in subjects with SAR.Methods: Subjects 12 years or older (n 5 429) with moderate-to-severe baseline symptoms were randomized to MFNS, 200 mgonce daily, or placebo in this 15-day, double-blind, parallel-group study. Subjects evaluated morning instantaneous TOSSsand daily reflective TOSSs, total nasal symptom scores (TNSSs;both instantaneous TNSSs and reflective TNSSs, respectively),and individual ocular and nasal symptoms. Mean changes frombaseline averaged over days 2 to 15 (instantaneous) and days1 to 15 (reflective) were calculated. Quality of life was assessedby using the Rhinoconjunctivitis Quality of Life Questionnaire.Results: MFNS treatment yielded significant reductions frombaseline versus placebo in instantaneous TOSSs (20.34,P 5 .026, coprimary end point), instantaneous TNSSs (20.88,P < .001, coprimary end point), reflective TOSSs (20.44,

From aAllergy Associates Medical Group, San Diego; bthe University of North Texas,

North Texas Health Science Center, Fort Worth; cthe Division of Immunology-Allergy,

Department of Internal Medicine, University of Cincinnati; and dMerck Research Lab-

oratories, Kenilworth.

Support was provided by Schering-Plough Research Institute, a division of Schering

Corporation.

Disclosure of potential conflict of interest: B. M. Prenner receives research support from

Abbot, Aerovent, Alcon, Amgen, Amphastar, Boehringer Ingelheim, Forrest,

Genentech, GlaxoSmithKline, Map Pharmaceuticals, Meda, Novartis, Pharmaxis,

Sanofi-Aventis, the Schering-Plough Research Institute, Sepracor, Skyepharma, UCB,

and Wyeth; has consultant arrangements with Abbott, Astellas, AstraZeneca,

Dynavax, Critical Therapeutics, Genentech, GlaxoSmithKline, King Pharmaceuticals,

Meda, Merck, Novartis, Protein Design Labs, Sanofi-Aventis, Schering-Plough, Sciele

Pharma, Stallergenes, and Teva; and is on the speakers’ bureau for Altana, Allergan,

Astra Zeneca, Astellas, Genentech, GlaxoSmithKline, Meda, Merck, Novartis, Sanofi-

Aventis, Sepracor, Schering-Plough, and Teva. B. Q. Lanier receives research support

from Alcon Labs, Schering Laboratories, Novartis, and Santofi; has consulted for

Alcon Laboratories on nasal antihistamine protocols; and is on the speakers’ bureau for

Novartis and Schering-Plough. D. I. Bernstein has consultant arrangements with

Schering-Plough and receives research support from Schering-Plough. A. Teper has

financial interests with Schering-Plough. T. Shekar has declared that he has no conflict

of interest.

Received for publication April 24, 2009; revised March 4, 2010; accepted for publication

March 4, 2010.

Available online May 3, 2010.

Reprint requests: Bruce M. Prenner, MD, Department of Pediatrics, UCSD School of

Medicine, 6386 Alvarado Ct #210, San Diego, CA 92120. E-mail: prenner@aaamg.

com.

0091-6749/$36.00

� 2010 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2010.03.004

P 5 .005), and reflective TNSSs (21.06, P < .001). Significantdecreases in all individual reflective ocular symptoms andinstantaneous eye itching/burning and eye watering/tearingwere observed for MFNS versus placebo (P < .05). Numericimprovements in instantaneous eye redness were seen but didnot reach statistical significance. Improvements inRhinoconjunctivitis Quality of Life Questionnaire total scoresand individual symptom domains were achieved with MFNStreatment versus placebo (P < .001). MFNS was well tolerated.Conclusion: This prospective study demonstrates that MFNSsignificantly reduces ocular symptoms in subjects with SAR.(J Allergy Clin Immunol 2010;125:1247-53.)

Key words: Allergic rhinitis, intranasal corticosteroids, mometasonefuroate nasal spray

Both nasal and ocular allergic responses in subjects withallergic rhinitis (AR) are characterized by an IgE-mediated early-phase reaction and, in approximately 50% of patients, a late-phasereaction.1 Mast cell degranulation, release of inflammatory medi-ators, and infiltration of inflammatory cells occur within the nasalmucosa and conjunctival epithelium,2-5 resulting in nasal symp-toms, such as congestion, rhinorrhea, sneezing, and nasal itching.Ocular symptoms (ie, itching, watering/tearing, and redness) oc-cur in up to 85% of subjects with AR.6-8 Ocular symptoms aremore prevalent in subjects with seasonal allergic rhinitis (SAR)than in those with perennial AR,7 and in a US survey of 2,500 pa-tients with AR, more than 50% of responders characterized ocularsymptoms as moderately to extremely bothersome.9 Nasal andocular symptoms both contribute to the negative effect thatSAR can have on quality of life through interference with sleep,productivity at school/work, and daily or social activities.7,10

Evidence-based management guidelines recommend intranasalcorticosteroids (INSs), which act on both early- and late-phasereactions of the immune response,11 as first-line therapy formoderate-to-severe AR8,12 and antihistamine or cromone eye dropsonly when ocular symptoms persist despite use of INSs or oralantihistamines.13 Ocular antihistamines have been shown tosuppress eye symptoms more effectively than INSs in allergen chal-lenge models,14,15 although such comparisons have not beenperformed under outdoor exposure conditions. In conjunctival chal-lenge studies, ocular antihistamines with mast cell–stabilizingactivity relieve eye symptoms significantly better than pure mastcell stabilizers,16,17 whereas clinical studies show comparable or su-perior efficacy between the 2 classes.18-20 Use of INSs with oralantihistamines also has been recommended based on potentially ad-ditive mechanisms of action.21,22 However, studies and 2 meta-analyses show no advantage in nasal or ocular symptoms withcombination therapy versus INS monotherapy.23-26 One clinical

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1248 PRENNER ET AL

Abbreviations used

AE: A

dverse event

ANCOVA: A

nalysis of covariance

AR: A

llergic rhinitis

FF: F

luticasone furoate

INS: In

tranasal corticosteroid

iTNSS: In

stantaneous total nasal symptom score

iTOSS: In

stantaneous total ocular symptom score

LS: L

east squares

MFNS: M

ometasone furoate nasal spray

RQLQ: R

hinoconjunctivitis Quality of Life Questionnaire

rTNSS: R

eflective total nasal symptom score

rTOSS: R

eflective total ocular symptom score

SAR: S

easonal allergic rhinitis

TNSS: T

otal nasal symptom score

TOSS: T

otal ocular symptom score

study of patients with SAR found combined therapy with a nasalantihistamine spray (azelastine) and an INS significantly reducedtotal nasal symptoms versus use of either treatment alone.27

Increasing evidence is emerging from retrospective and pro-spective studies for the efficacy of INSs in reducing the ocularsymptoms of SAR.28-31 Overall, INSs are recommended as themost effective medication for AR, more comprehensively cover-ing allergic symptoms,12 with the advantages of single-agenttreatment, such as better patient adherence, cost-effectiveness,and reduced risk for side effects.5

Mometasone furoate nasal spray (MFNS) is a potent, topicallyactive corticosteroid and an established treatment for the nasalsymptoms of AR.32-34 Recently, MFNS has demonstrated reduc-tions in the total ocular symptom score (TOSS) and individual oc-ular symptoms versus placebo in retrospective analyses of datafrom individual35-37 and pooled38,39 phase III, randomized, con-trolled studies of subjects with SAR in which nasal symptomswere primary end points and ocular symptoms were not entrycriteria, including further subanalysis of subjects withmoderate-to-severe baseline ocular symptoms.39

The objective of the present study was to evaluate prospectivelythe efficacy of once-daily MFNS versus placebo in reducingTOSSs and individual ocular symptoms in subjects with SARwhile confirming the proved efficacy of the agent in reducingnasal symptoms of SAR.

METHODS

Study design and subjectsThis was a multicenter, phase III, randomized, double-blind, parallel-group

study conducted from April through July 2007 at 25 physicians’ offices in the

United States in compliance with the principles of good clinical practice and

other local, regional, and national regulations. The clinical protocol was

reviewed and approved by a central institutional review board or independent

ethics committee at each participating site. All subjects (or their legal

representative) were required to provide written informed consent before

study participation.

Subjects meeting eligibility criteria (Table I) entered a screening period

(>_3 days, visit 1, see Fig E1 in this article’s Online Repository at www.

jacionline.org) and completed twice-daily diaries documenting SAR symp-

toms, adverse events (AEs), and use of concomitant medications. On the

morning of the baseline visit (visit 2), clinically symptomatic subjects, defined

by summed morning and evening symptom scores from the 3 days before

baseline plus morning scores from the baseline visit (rhinorrhea, >_14; nasal

congestion, >_14; total nasal symptom score [TNSS], >_42; and TOSS, >_28),

were randomized sequentially in a 1:1 ratio by using a computer-generated

randomization schedule to receive MFNS, 200 mg once daily (two 50-mg

sprays per nostril at approximately the same time each morning), or matching

vehicle placebo nasal spray for 15 days. Subjects administered the first dose of

treatment at the study center (visit 2) after training in correct use of the nasal

spray. Use of any other prescription or over-the-counter medications (eg, an-

tihistamines and salines) potentially affecting ocular or nasal symptoms was

not permitted during the study.

Outcome assessmentsSubjects rated the severity of their individual symptoms, including rhinor-

rhea, nasal congestion, nasal itching, sneezing, redness of eyes, itching/

burning eyes, and tearing/watering eyes, on a 4-point scale (ie, 0, none; 1, mild;

2, moderate; and 3, severe) twice daily in subject diaries (in the morning before

dosing and approximately 12 hours later [in the evening]). Instantaneous and

reflective (over the previous 12 hours) scores were captured. Instantaneous

TNSSs (iTNSSs) and TOSSs (iTOSSs) were derived by summing instanta-

neous morning individual symptom scores. Daily reflective scores (reflective

TNSSs [rTNSSs] and reflective TOSSs [rTOSSs]) were obtained from

averaging the reflective morning and evening individual symptom scores.

The 2 coprimary end points of the study were change from baseline in

iTNSSs and iTOSSs, each averaged over days 2 to 15. Key secondary end

points included change from baseline in daily rTNSSs and rTOSSs averaged

over days 1 to 15 and instantaneous nasal congestion scores averaged over days

2 to 15 and change from baseline to study end point in the Rhinoconjunctivitis

Quality of Life Questionnaire (RQLQ) total score. Additional end points were

change from baseline in instantaneous and reflective individual symptom

scores and subject and investigator evaluations of overall condition (rated at

the 4 study visits [see Fig E1] by using a 4-point scale, as above) and therapeu-

tic response to study medication (assessed at visits 3 and 4 by using a 5-point

scale: 1, complete relief; 2, marked relief; 3, moderate relief; 4, slight relief;

and 5, no relief). The same study investigator or his or her qualified designee

(subinvestigator) conducted all clinical assessments/reviews.

At visits 1 and 4, subjects aged 18 years or older completed the RQLQ before

all other assessments (28 questions in 7 domains: activities, sleep, non–nose/eye

symptoms, practical problems, nasal symptoms, eye symptoms, and emotions,

each rated on a 7-point scale from 0 [not troubled] to 6 [extremely troubled]).40

The total score was the mean of all 28 questions. Domain scores were the mean

scores of questions within each domain. The established minimal important dif-

ference for RQLQ total score is 0.5, whereby any greater change in scores is

considered a clinically significant improvement in subject quality of life.41

A physical examination and 12-lead electrocardiogram were completed at

screening. Vital signs and AEs were recorded at visits 2, 3, and 4. Pollen counts

were recorded at each study center 3 or more times per week for the study’s

duration.

Statistical analysisA sample size of 230 for each treatment arm was calculated to allow

detection of a difference in iTOSSs between treatment groups of 0.55 points or

more with a power of 90%, assuming a pooled SD of 1.8 points in change from

baseline and a 2-sided a value of .05. A sample size of 230 subjects per

treatment group and a difference between the MFNS and placebo groups in

iTNSS of 0.8 points, assuming an SD of 2.1 points, will have a power of 98%.

Assuming independent coprimary end points, the joint power for coprimary

end points was estimated at approximately 88% by computing the product of

the 2-power estimates.

Efficacy and safety analyses encompassed the intent-to-treat population,

including all randomized subjects. Subjects with a missing evaluation at a

given time point were omitted from the analysis for that specific assessment.

End point values were defined as the postbaseline nonmissing observation

carried forward, regardless of the visit windows. The coprimary end points

were tested by using an analysis of covariance (ANCOVA) model, with

treatment study center and baseline as covariates. Comparisons between the

MFNS and placebo groups were made from the least-squares (LS) mean

TABLE I. Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

>_12 y of age History of anaphylaxis, other severe local reactions, or both to skin prick

testing

>_2-y history of SAR with symptom exacerbation during the study season Corticosteroid-dependent asthma

Positive skin prick test response at screening (defined as a wheal diameter>_3 mm greater than that produced in response to diluent control) in

response to an appropriate seasonal allergen

Current or prior frequent, clinically significant sinusitis, or chronic, purulent

postnasal drip

Clinically symptomatic (as assessed by diary records) at screening:

rhinorrhea, >_2; nasal congestion, >_2; TNSS (sum of individual symptom

scores for rhinorrhea, nasal congestion, nasal itching, and sneezing) >_6

(moderate-to-severe), TOSS (sum of individual symptom scores for ocular

itching, tearing/watering, and ocular redness) >_4, and overall evaluation of

SAR >_2 (moderate)

Significant comorbid medical conditions/diseases that could interfere with

completion of study diaries, effect on the metabolism of study medication,

or require treatment

Female subjects: negative serum pregnancy test result at screening, not

currently nursing, and use of a medically acceptable form of birth control

for duration of the study

Upper respiratory tract/sinus infection, requiring a course of antibiotics not

complete within >_14 d of the screening visit or viral upper respiratory tract

infection <_7 d before screening

Rhinitis medicamentosa

Nasal abnormalities that could interfere with nasal air flow

Dependency on nasal, ocular, or oral decongestants; nasal antihistamines; or

nasal steroids

History of allergies to >_2 classes of medications or intolerance to nasal

sprays

Subjects receiving immunotherapy, unless on regular maintenance schedule

before screening and for duration of the study

SAR, Seasonal allergic rhinitis.

TABLE II. Baseline subject demographics and characteristics (all

randomized subjects)

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PRENNER ET AL 1249

calculated from the ANCOVA by using the pooled SD, with a 2-sided a value of

.05. Secondary end points were analyzed with a similar ANCOVA model.

MFNS, 200 mg QD

(n 5 220)

Placebo

(n 5 209)

Age (y), mean 6 SD 34.5 6 14.1 36.8 6 14.5

Age group distribution, no. (%)

6 to <12 y 0 1 (<1)

12 to <18 y 31 (14) 24 (11)

18 to <65 y 184 (84) 181 (87)>_65 y 5 (2) 3 (1)

Sex, no. (%)

Male 88 (40) 84 (40)

Female 132 (60) 125 (60)

Race, no. (%)

White 166 (75) 156 (75)

Black 43 (20) 44 (21)

RESULTS

Study populationOf 656 subjects screened, 429 were randomized (MFNS [200

mg once daily] group, n 5 220; placebo group, n 5 209),and 420 (98%) subjects completed the study. Reasons fordiscontinuation were AEs (MFNS group, 1%; placebo group,0.48%), noncompliance with protocol (MFNS group, 1%;placebo group, 0.48%), treatment failure (MFNS group, 0;placebo group, 0.48%), consent withdrawal (MFNS group,0; placebo group, 0.48%), and protocol violation (MFNS group,0; placebo group, 0.48%). Demographic and baseline character-istics were comparable between the treatment groups (Table II).

Other 11 (5) 9 (4)

Mean 6 SD body

mass index (kg/m2)

27.45 6 6.91 28.55 6 6.93

Mean 6 SD iTNSS 9.39 6 1.68 9.42 6 1.57

Mean 6 SD rTNSS 9.79 6 1.44 9.82 6 1.51

Mean 6 SD iTOSS 6.84 6 1.43 6.81 6 1.58

Mean 6 SD rTOSS 6.95 6 1.34 6.93 6 1.43

iTNSS, Instantaneous total nasal symptom score; iTOSS, instantaneous total ocular

symptom score; MFNS, mometasone furoate nasal spray; QD, once daily; rTNSS,

reflective total nasal symptom score; rTOSS, reflective total ocular symptom score;

SD, standard deviation.

Efficacy in ocular symptomsFor the coprimary end point of change from baseline in iTOSSs

averaged over days 2 to 15, MFNS demonstrated a significantreduction versus placebo (21.71 [225.1%] vs 21.37 [220.1%],P 5 .026), with a treatment difference of 20.34 (95% CI, 20.65to 20.04; Fig 1 and see Table E1 in this article’s Online Reposi-tory at www.jacionline.org). LS mean change from baseline inrTOSS averaged over days 1 to 15 was also significantly greaterwith MFNS than with placebo (21.93 [227.4%] vs 21.49[220.9%], P 5 .005, Fig 1 and see Table E1).

MFNS showed significantly greater improvements versusplacebo from baseline in individual instantaneous ocular symp-toms of itching/burning and watering/tearing (P < .05 for both).Mean change from baseline in instantaneous eye redness scorewas numerically but not significantly greater with MFNS versusplacebo (Fig 1 and see Table E1). All individual reflective ocular

symptom scores significantly improved with MFNS versus pla-cebo (P < .05 for all, Fig 1 and see Table E1).

Efficacy in nasal symptomsSubjects treated with MFNS reported significantly greater

reductions in iTNSSs (the coprimary end point), rTNSSs, and allindividual instantaneous and reflective nasal symptom scores

FIG 1. Mean change from baseline averaged over days 2 to 15 in total and individual instantaneous (A) and

reflective (B) ocular symptoms (all randomized subjects). Brackets represent SEMs. *P < .05 versus placebo.

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1250 PRENNER ET AL

versus those treated with placebo. LS mean change from baselineaveraged over days 2 to 15 for the iTNSS was 22.54 (226.4%)with MFNS versus 21.66 (216.9%, P < .001) for placebo, with atreatment difference of 20.88 (95% CI, 21.27 to 20.51; see FigE2, A, in this article’s Online Repository at www.jacionline.org).LS mean change from baseline averaged over days 1 to 15 for therTNSS was 22.88 (228.6%) for MFNS versus 21.82 (217.4%,P < .001) for placebo, with a treatment difference of 21.06 (95%CI, 21.45 to 20.68; see Fig E2, B).

Overall condition of SARGreater improvements in overall SAR condition from baseline

to study end were seen with MFNS treatment versus placebowhen rated by investigators (mean change of 231.3% for MFNSvs 221.7% for placebo; LS mean difference of 20.31 [95% CI,20.45 to 20.16]; P < .001) and subjects (mean change of233.6% for MFNS vs 220.4% for placebo; LS mean treatmentdifference of 20.35 [95% CI, 20.50 to 20.21]; P < .001).

Therapeutic responseAs per the 5-point scale, at the study’s end, the MFNS group

showed significantly greater response to therapy versus theplacebo group, as reported by both subjects (LS mean of 3.14for MFNS vs 3.67 for placebo, P < .001) and investigators (LSmean of 3.24 for MFNS vs 3.66 for placebo, P < .001). The dif-ference in symptom relief between treatments was observedfrom the first postbaseline assessment (day 8) onward by bothsubjects (P 5 .001) and investigators (P < .001).

Quality of lifeIn subjects treated with MFNS, total RQLQ scores decreased

by 41.5% versus 23.4% with placebo (see Table E2 in this article’sOnline Repository at www.jacionline.org). The LS mean treat-ment difference of 20.73 for MFNS versus placebo (95% CI,21.01 to 20.45; P < .001) suggests clinically meaningfulquality-of-life improvements with MFNS treatment. The minimalimportant difference was also within the established threshold

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value of greater than 0.5 for MFNS versus placebo in all individ-ual RQLQ domains (all P < .001).

Safety and tolerabilityMFNS treatment was well tolerated. Incidence of treatment-

emergent AEs was low (14.5% in the MFNS group vs 12.0% withplacebo). The only AE reported by more than 2% of subjects ineither group was headache (5 subjects in each group, 2.3%). AEsconsidered by investigators to be related to study medication werereported for 11 (5%) subjects in the MFNS group (13 AEs) and 7(3.3%) subjects in the placebo group (7 AEs). The most commontreatment-related side effects were epistaxis (MFNS, n 5 4[1.8%]; placebo, n 5 1 [0.5%]) and nasal discomfort (MFNS, n 5 4[1.8%]; placebo, n 5 0 [0%]). No serious AEs were reported ineither group.

Pollen countMean pollen counts captured over the study period and

averaged across 25 study sites in a wide geographic area areshown in Fig E3 (available in this article’s Online Repository atwww.jacionline.org).

DISCUSSIONThe efficacy of MFNS as first-line AR treatment has been

demonstrated in several randomized, placebo-controlled studies,regardless of symptom severity.32-34 However, the effectivenessof MFNS in reducing ocular symptoms has previously onlybeen shown by means of retrospective and pooled analyses ofdata from studies designed with nasal symptoms as the primaryend point; this is the first study prospectively evaluating ocular ef-fects. Consistent with previous studies assessing nasal symptoms,subjects receiving MFNS, 200 mg once daily, reported significantreductions in TOSSs sustained over the 24-hour dosing interval.

INSs directly inhibit nasal inflammation after nasal allergenchallenge in subjects with AR11,42; however, it is less clear howINSs alleviate ocular symptoms. Compared with inhaled or oralcorticosteroids, INSs demonstrate minimal effects on intraocularpressure, suggesting that relief of ocular symptoms is not from di-rect effects on the eye by means of transport through the nasolac-rimal duct or through systemic absorption.11,43-45 Some authorshave suggested that ocular symptoms are primarily caused by in-creased indirect activity in naso-ocular reflex pathways and onlysecondarily by means of direct allergen exposure to the eye.46 Thepresence of a naso-ocular reflex pathway is supported by theobservation that nasal application of capsaicin results inimmediate-onset lacrimation followed by tachyphylaxis.47 Atten-uation of nasal and ocular allergy symptoms after CO2 inhalation,which inhibits neuronal activation in vitro, is also consistent witha nerve reflex pathway, perhaps at the level of the trigeminal gan-glion.48-50 In addition, histamine, which is released at the chal-lenge site, has been shown to increase activity in nerve fibers.51

Unilateral nasal challenge stimulates nasal, but not ocular, hista-mine release along with bilateral ocular itching and tearing; thesesymptoms are blocked by prechallenge administration of intrana-sal antihistamine.52,53 These results support the hypothesis thatincreased nasal histamine after nasal allergen challenge stimu-lates a cholinergic reflex pathway causing ocular symptoms,and INS treatment attenuates ocular symptoms by modulating

these reflex pathways. In nasal allergen challenge studies INSs re-duce levels of neurally active inflammatory mediators, includinghistamine and bradykinin, in nasal secretions, which might alsoreduce excess stimulation of this naso-ocular reflex, improvingocular symptoms.30,54,55 INSs might also reduce allergen reten-tion in the conjunctiva by improving drainage of inflammatorymediators through the nasolacrimal ducts.29 The mucosa of pa-tients with AR might thicken sufficiently to occlude the nasolac-rimal duct opening beneath the inferior turbinate,56 and INStreatment has been found to reduce tearing in patients with ac-quired epiphora.57 Significant reductions in TOSSs and conges-tion seen in the present study are consistent with thismechanism of enhanced drainage: reductions in rTOSSs and re-flective nasal congestion scores were 27.8% and 26.6%, respec-tively, in the MFNS group and 21.6% and 15.5%, respectively,in the placebo group; iTOSSs and instantaneous nasal congestionscores were decreased by 25.2% and 22.7%, respectively, in theMFNS group and 20.3% and 14.9%, respectively, in the placebogroup. Placebo nasal spray might also remove mediators from thenasal mucosa through flushing, which suggests a mechanism forthe well-documented improvements in nasal symptoms with vehi-cle placebo.29,58 This reduction of inflammatory mediators in thenose might decrease stimulation of the naso-ocular reflex,52,54

leading to the improvements in ocular symptoms observed withplacebo in the present study.

The significant decrease in iTOSSs, rTOSSs, and reflectiveindividual symptoms with MFNS treatment are generally similarto those of other prospective studies of INSs for the treatment ofocular symptoms.29-31 However, only one of these prospectivestudies assessed the TOSS as the primary end point, and only re-flective scores were evaluated.29 Subjects with AR are generallymore symptomatic during the morning,59 and therefore instanta-neous morning scores are an important measure of treatment effi-cacy. Although this study was not powered to assess differences inindividual symptoms, significant and sustained improvements ininstantaneous morning scores for eye itching/burning and water-ing/tearing were observed with MFNS treatment, demonstratingefficacy over the 24-hour dosing interval. Numeric improvementsin morning redness scores were also seen but were not statisticallysignificant. In a recent comprehensive article by Keith and Scad-ding,60 several INS agents (budesonide, beclomethasone dipropi-onate, fluticasone furoate [FF], fluticasone propionate, MFNS,and triamcinolone acetonide) were found to have positive effectson relieving ocular symptoms of SAR,60 and several authorshave suggested that the ocular efficacy of INS agents is a classeffect rather than an attribute of a single agent.61,62

Class-based ocular effects on individual morning symptomsare less established. In 5 recent placebo-controlled studies, FFsignificantly improved iTOSSs.30,31,63-65 However, the absence ofdata for individual ocular symptoms in 4 of these studies has beencited as a weakness in their findings.66 One study did show that FFsignificantly improved all individual morning symptoms.30 It isinteresting to note that in a study of patients with perennial AR,FF significantly improved morning ocular itching and tearingbut not redness.67

Explanations for the relatively lower treatment effect of INSson morning redness merits further study; however, differentialexpression of the ocular late-phase response and infiltration ofinflammatory cells and increased inflammatory mediators severalhours after conjunctival allergen exposure2,68 might contribute.Redness is a predominant late-phase symptom4 that might not

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1252 PRENNER ET AL

respond well to an intranasally localized agent. Additionally,elimination of inflammatory mediators through the nasolacrimalduct likely decreases while patients are supine.

Until there are head-to-head studies of INSs in the treatment ofocular symptoms, study-specific variables that can affect out-comes, such as baseline severity and allergen exposure, must beconsidered when comparing results. In the present study, baselinerTOSSs and iTOSSs ranged from 6.7 to 6.9 in the active andcontrol arms, indicating moderate-to-severe symptoms. Previousstudies in monosensitive subjects have reported a pollen count ofbetween 10 to 30 grains/m3 during screening, followed by asteady decrease throughout the study period.30,31 In this study,interpreting variations in pollen levels is complex because of in-clusion of polysensitive subjects from different geographic areaswho were enrolled in the trial on an ongoing basis. To addressthese variances, future clinical trials evaluating INSs should in-clude the collection of such data as pollen counts and time sub-jects spend outdoors.

The present study demonstrated significant improvements insubjects’ health-related quality of life over the 2-week MFNStreatment period, with clinically meaningful improvements indomains ranging from sleep difficulties to emotional problems,including frustration and irritability.69

In conclusion, this first prospective study demonstrates thatonce-daily MFNS is effective in reducing ocular symptoms insubjects with moderate-to-severe SAR. A 24-hour duration ofeffect was observed for total nasal and ocular symptoms.Additionally, subjects experienced clinically meaningful im-provements in health-related quality of life. As with nasalcongestion associated with AR, these findings suggest thatMFNS can be considered as a single effective treatment to beused as a first-line monotherapy for the symptoms of SAR,including moderate-to-severe nasal congestion and ocularsymptoms.

Editorial support was provided by Karl Torbey, MD, of AdelphiEden Health

Communications. This support was funded by Schering Corporation. Schering

Corporation is a subsidiary of Merck & Co.

Clinical implications: Patients with SAR frequently experienceocular symptoms and typical nasal symptoms. MFNS provideseffective treatment for both nasal and ocular symptoms.

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FIG E1. Study design. *Screening period of at least 3 days. �Randomization. MFNS, Mometasone furoate

nasal spray; QD, once daily.

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FIG E2. Mean change from baseline averaged over days 2 to 15 in total and individual instantaneous (A) and

reflective (B) nasal symptoms (all randomized subjects). Brackets represent SEMs. *P < .001 versus placebo.

MFNS, Mometasone furoate nasal spray; QD, once daily.

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FIG E3. Mean pollen count averaged over 25 sites during the study period.

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TABLE E1. Mean change from baseline in total and individual ocular symptom scores (all randomized subjects)

Reflective Instantaneous

MFNS,

200 mg QD

(n 5 220)

Placebo

(n 5 208)

Difference in

treatment effect

(DMFNS 2

Dplacebo) 95% CI

P

value

MFNS,

200 mg QD

(n 5 220)

Placebo

(n 5 208)

Difference in

treatment effect

(DMFNS 2

Dplacebo) 95% CI

P

value

TOSS

LS mean baseline

(SE)

6.94 (0.10) 6.90 (0.10) 6.78 (0.10) 6.74 (0.11)

LS mean change

from baseline

(SE)

21.93 (0.12) 21.49 (0.12) 20.44 20.75 to

20.13

.005 21.71 (0.11) 21.37 (0.12) 20.34 20.65 to

20.04

.026

Eye itching/burning

LS mean baseline

(SE)

2.46 (0.03) 2.42 (0.04) 2.39 (0.04) 2.36 (0.04)

LS mean change

from baseline

(SE)

20.68 (0.04) 20.49 (0.04) 20.19 20.29 to

20.08

<.001 20.60 (0.04) 20.46 (0.04) 20.14 20.25 to

20.03

.01

Eye redness

LS mean baseline

(SE)

2.17 (0.04) 2.19 (0.05) 2.12 (0.04) 2.17 (0.05)

LS mean change

from baseline

(SE)

20.58 (0.04) 20.47 (0.04) 20.11 20.21 to

2<0.01

.046 20.48 (0.04) 20.43 (0.04) 20.05 20.17 to

0.05

.316

Eye tearing/watering

LS mean baseline

(SE)

2.31 (0.04) 2.29 (0.04) 2.27 (0.04) 2.21 (0.05)

LS mean change

from baseline

(SE)

20.68 (0.04) 20.53 (0.04) 20.15 20.26 to

20.03

.013 20.63 (0.04) 20.48 (0.05) 20.15 20.26 to

20.03

.011

D, LS mean change from baseline; CI, Confidence interval; LS, least-squares; MFNS, mometasone furoate nasal spray; QD, once daily.

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TABLE E2. Mean change from baseline to end point in RQLQ scores

MFNS (n 5 189) Placebo (n 5 182)

RQLQ scores BL D from BL to end point BL D from BL to end point

Total 4.27 21.81* (41.5%) 4.28 21.08 (23.4%)

Sleep 4.12 21.84* (37.2%) 4.17 21.15 (24.5%)

Non–nose/eye symptoms 3.97 21.59* (37.8%) 3.95 20.96 (15.4%)

Total practical problems 4.62 22.13* (43.9%) 4.65 21.14 (22.7%)

Total nasal symptoms 4.74 22.06* (41.6%) 4.78 21.16 (23.0%)

Total eye symptoms 4.37 21.84* (39.9%) 4.45 21.25 (25.1%)

Emotion 3.88 21.75* (44.2%) 3.82 21.05 (23.9%)

Total activity 4.50 21.72* (37.6%) 4.47 20.94 (17.1%)

BL, Baseline; MFNS, mometasone furoate nasal spray; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire.

*P < .001 vs placebo.

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