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`Clinical Therapeutics/Volume 27, Number 5, 2005
`This material may beprotcetcd by Copyrightlaw(Title 17 U.S. Code)
`
`
`Effectiveness of Azelastine Nasal Spray Compared with Oral
`Cetirizine in Patients with Seasonal Allergic Rhinitis
`
`Jonathan Corren, MD"; William Storms, MD?; Jonathan Bernstein, MD°;
`William Berger, MD*; Anjuli Nayak, MD°; and Harry Sacks, MD®, for
`the Azelastine Cetirizine Trial No. 1 (ACT 1) Study Group*
`‘Allergy Research Foundation, Inc., Los Angeles, California; @Asthma and Allergy Associates, PC, Colorado
`Springs, Colorado; *Bernstein Clinical Research Center, Cincinnati, Ohio; “Southern California Research,
`Mission Viejo, California; “Sneeze, Wheeze & Itch Associates, Normal, Illinois; and *MedPointe
`Pharmaceuticals, Somerset, NewJersey
`
`ABSTRACT
`Background: Azelastine nasal spray and oralcetiri-
`zine are selective histamine H,-receptor antagonists
`that are approved in the United States for the treat-
`mentof seasonal allergic rhinitis (SAR).
`Objective: The objective of the present study was
`to comparetheefficacy and tolerability of azelastine
`nasal spray administered at the recommended dosage
`of 2 sprays per nostril twice daily with those of cetiri-
`zine in the treatment of moderate to severe SAR.
`Methods: This multicenter,
`randomized, double-
`blind, parallel-group, 2-week comparative study was
`conducted during the 2004fall allergy season in patients
`with moderate to severe SAR. After a 1-week placebo
`lead-in period, patients were randomizedto receive azel-
`astine nasal spray 2 sprays per nostril twice daily plus
`placebo tablets or cetirizine 10-mg tablets once daily
`plus a placebosaline nasal spray for the 2-week double-
`blind treatment period. The primary efficacy variables
`were (1) change from baseline to day 14 in the 12-hour
`reflective total nasal symptom score (TNSS), which com-
`bines scores for rhinorrhea, sneezing, itchy nose, and nasal
`congestion, and (2) onset of action, based on the instan-
`taneous TNSS over 4 hours after the first dose of study
`drug. During the double-blind treatment period, patients
`recorded their symptom scores on diary cards twice
`daily (morning and evening). Patients aged 218 years
`also completed the Rhinoconjunctivitis Quality of Life
`Questionnaire (RQLQ)at baseline and on day 14.
`Results: Three hundred seven patients were ran-
`domized to treatment, and 299 completed 2 weeks of
`study treatment. The age of the population ranged
`from 12 to 74 years (mean, 35 years), 62.9% werefe-
`male, and 69.6% were white. Over 2 weeks of treat-
`ment, both groups had significant improvements in
`
`the:TNSSS compared with baseliine(P < 0.001). The
`overall change in TNSS wassignificantly greater with
`azelastine nasal spray compared with cetirizine
`(29.3% vs 23.0% improvement,
`respectively; P =
`0.015). In terms of onset of action, azelastine nasal
`spray significantly improved the instantaneous TNSS
`compared with cetirizine at 60 and 240 minutesafter
`the initial dose (both, P = 0.040). Scores on each do-
`main of the RQLQ weresignificantly improved in
`both groups compared with baseline (P < 0.001); the
`overall RQLQ score wassignificantly improved with
`azelastine nasal spray compared with cetirizine (P =
`0.049). Both treatments were well tolerated.
`Conclusion: In this 2-week study in patients with
`moderate to severe SAR, azelastine nasal spray was
`well tolerated and produced significantly greater im-
`provements in TNSSandtotal RQLQ score compared
`with cetirizine. (Clin Ther. 2005;27:543-553) Copyright
`© 2005 Excerpta Medica,Inc.
`Key words: azelastine nasal spray, cetirizine, aller-
`gic rhinitis, double-blind clinicaltrial.
`
`INTRODUCTION
`Azelastine nasal sprayt is a topical second-generation
`antihistamine indicated for the treatment of seasonal
`
`*Members ofthe study group arelisted in the Acknowledgments.
`tTrademark: Astelin® (MedPointe Pharmaceuticals, Somerset,
`New Jersey).
`
`Accepted for publication April 8, 2005.
`Express track online publication April 28, 2005.
`doi:10.1016/j.clinthera.2005.04.012
`0149-2918/05/$19.00
`
`Printed in the USA. Reproduction in whole or part is not permitted.
`Copyright © 2005 Excerpta Medica, Inc.
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`
`(SAR) and nonallergic vasomotor
`allergic rhinitis
`rhinitis. The active ingredient, azelastine hydrochlo-
`ride, is a high-affinity histamine H,-receptor antago-
`nist with potency at the H,-receptor site ~10 times
`greater than that of chlorpheniramine.! In addition
`to histamine antagonism, azelastine has been shown
`in clinical
`studies to have inhibitory effects on
`leukotrienes,? bradykinin and substance P23 cyto-
`kines,* intercellular adhesion molecule-1 (ICAM-1)
`expression,’ and eosinophil chemotaxis.’ Cetirizine
`hydrochloride* is an oral second-generation antihista-
`mine indicated for the treatment of SAR,perennial al-
`lergic rhinitis, and chronic urticaria. It is a selective
`H,-receptor antagonist® that has been shownto inhib-
`it leukotriene’ and prostaglandin production,® as well
`as ICAM-1expression and eosinophil chemotaxis.”
`In clinical studies, cetirizine has been compared
`with other oral second-generation antihistamines, in-
`cluding loratadine and fexofenadine. In two 2-day,
`placebo-controlled studies in an environmental expo-
`sure unit!!! and in a 2-day outdoorstudy,'2 cetirizine
`10 mg once daily was more effective than loratadine
`in improving nasal symptomsin patients with SAR
`(P < 0.05). In two 2-week, multicenter studies compar-
`ing cetirizine 10 mg once daily with fexofenadine 120
`and 180 mg oncedaily, there were nosignificant differ-
`ences in efficacy betweencetirizine and the 2 fexofena-
`dine doses.!3:!4 However,
`in another environmental
`exposure unit study,! cetirizine wassignificantly more
`effective than fexofenadine during the 24-hour interval
`after initial administration (P < 0.001).
`Comparative studies of azelastine nasal spray have
`been carried out in Europeat a dosage of 1 spray per
`nostril twice daily, one half the recommended adult
`dosage in the United States. In a 2-week, double-blind
`study of azelastine nasal spray and intranasal beclo-
`methasone in patients with SAR,!° both treatments
`significantly improved symptom scores compared
`with placebo (P < 0.001), and there were nosignifi-
`cant differences between treatment groups.
`In a
`2-week, double-blind study in patients with SAR,azel-
`astine nasal spray and cetirizine decreased nasal symp-
`tom scores by 60% and 63%, respectively, with no
`significant differences between treatments.!7 In addi-
`tion,
`the results of placebo-controlled studies have
`indicated that azelastine nasal spray at a dosage of
`2 sprays pernostril twice daily waseffective in patients
`
`“Trademark: Zyrtec® (Pfizer Inc., New York, New York).
`
`who remained symptomatic after treatment with lor-
`atadine!® or fexofenadine.!9
`Given the preceding findings, the objective of the
`present study wasto directly compare the efficacy and
`tolerability of azelastine nasal spray administered at
`the US recommended dosage of 2 sprays per nostril
`twice daily with those of cetirizine in the treatment of
`moderate to severe SAR.
`
`PATIENTS AND METHODS
`This was a randomized, double-blind, parallel-group,
`2-week comparative trial conducted during the 2004
`fall allergy season at 20 investigational research cen-
`ters distributed throughout the major geographic re-
`gions of the United States.
`
`Inclusion and Exclusion Criteria
`Studyinvestigators selected patients from their prac-
`tices and/or recruited volunteers to participate in the
`study. Eligible patients were male and female patients
`aged 212 years with at least a 2-year history of SAR and
`a documented positive allergy skin test, either intrader-
`mal or epicutaneous, during the previousyear. Patients
`were excluded for the following reasons: use of con-
`comitant medication(s) that could affect the assessment
`of efficacy of study treatment; any medical orsurgical
`condition that could affect
`the metabolism of study
`medications; clinically significant nasal disease (other
`than SAR)orsignificant nasal structural abnormalities;
`respiratory infection or other infection requiring antibi-
`otic therapy within 2 weeksofthe single-blind placebo
`lead-in period; past or current alcohol or drug abuse;
`and significant pulmonary disease, including persistent
`asthma requiring use of controller medication. Women
`of childbearing potential not using an accepted method
`of contraception and women who were pregnant or
`nursing also were excluded.
`
`Study Design
`This was a randomized, double-blind,parallel-group
`clinical trial designed to be consistent with a draft guid-
`ance from the US Food and Drug Administration for
`the conduct ofclinical trials in allergic rhinitis.2° A
`computer-generated randomization schedule was used
`to assign eligible patients to the 2 treatment groups in
`blocks of 4. The randomization schedule was provid-
`ed by a biostatistical group employed by the sponsor,
`and access to the code was confidential and accessible
`only to authorized persons not involved in the study.
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`Blinding of the study was preserved at each studysite
`until all patients had completed the study and the data-
`base waslocked.
`The study began with a 1-week, single-blind lead-
`in period, before which all previous allergy medica-
`tions were discontinued (oral antihistamines for a
`minimum of 5 days andintranasalsteroids for a min-
`imum of 14 days before the start of the period) and
`patients received placebo nasalspray and placebo cap-
`sules. Patients qualified for entry into the lead-in peri-
`od if they had a total nasal symptom score (TNSS) of
`>8 and a nasal congestion score 22 over the previous
`12 hours (12-hour reflective TNSS).2° The TNSS is a
`combined measure of the severity of nasal itching,
`nasal congestion, runny nose, and sneezing, each rated
`twice daily (morning and evening) on a 4-point scale
`(0 = none, 1 = mild, 2 = moderate, 3 = severe), with a
`maximum daily score of 24. Patients recorded their
`morning and evening 12-hour reflective symptom
`severity scores on diary cards for use by the investiga-
`tor in determining their eligibility to enter the double-
`blind treatment period.
`To be eligible for entry into the double-blind treat-
`ment period, patients must have recorded a morning
`or evening TNSS 28 on at least 3 days during the lead-
`in period and a morning or evening nasal congestion
`score of 3 on at least 3 days. For both the TNSS and
`nasal congestion score, 1 of the 3 pertinent days must
`have occurred within 2 days of the first day of the
`double-blind treatment period. In addition, because of
`the onset-of-action assessment (described in the follow-
`ing section), patients were required to have a TNSS 28
`on the morning of randomization; patients who were
`not sufficiently symptomatic at that time were asked
`to return the next day for the onset-of-action assess-
`ment. Patients who did not meet the minimum symp-
`tom severity score at this time were noteligible for
`randomization. Patients who continued to meet the
`study inclusion criteria and met the minimum TNSS
`and nasal congestion criteria were randomized to re-
`ceive treatment with azelastine nasal spray 2 sprays
`per nostril
`twice daily (morning and evening) plus
`placebo tablets (morning) or cetirizine 10-mg tablets
`once daily (morning) plus placebo saline nasal spray
`2 sprays per nostril twice daily (morning and evening)
`for 2 weeks (days 1-14).
`Azelastine nasal spray and placebo nasal spray were
`supplied by the manufacturer in spray-pump bottles of
`identical appearance. The placebo spray, which con-
`
`J. Corren et al.
`
`sisted of benzalkonium chloride, edetate disodium, hy-
`droxypropyl methylcellulose, citric acid, dibasic sodi-
`um phosphate, and sodiumchloride in purified water
`at pH 6.8 + 0.3, was identical to the vehicle formula-
`tion contained in azelastine nasal spray. To mask their
`identity, the cetirizine 10-mg tablets were encapsulated
`in gelatin capsules size DB#C and overfilled with lac-
`tose. Placebo capsules were filled only with lactose.
`The dissolution rates of the cetirizine 10-mg tablets
`and encapsulated cetirizine 10-mg tablets overfilled
`with lactose were shownto beessentially identical at
`the 20- and 30-minute (100%dissolution) time points
`at 37°C in a comparative dissolution assay performed
`by McKessonBioservices, Rockville, Maryland (Med-
`Pointe Pharmaceuticals, data on file), A placebo control
`group was not used in this study because both azelas-
`tine nasal spray and cetirizine have been shown to be
`safe and effective for the treatment of SAR.
`The study was approved by Sterling Institutional
`Review Board, Atlanta, Georgia. All patients or their
`guardians(if aged <18 years) signed the approved in-
`formed consent agreement before participation.
`
`Efficacy and Safety Variables
`The coprimary efficacy variables were change from
`baseline to day 14 in the severity of rhinitis symptoms
`based on the combined morning and evening 12-hour
`reflective TNSS, and onset of action, based on the
`change from baseline in the instantaneous TNSSrecord-
`ed in the physician’s office immediately before the first
`dose of study medication and at 30, 45, 60, 90, 120,
`150, 180, 210, and 240 minutes thereafter. Secondary
`efficacy variables were the change in TNSS from base-
`line to day 2 (end of the 24-hour dosing interval), and
`the change from baseline to day 14 in quality-of-life pa-
`rameters for patients aged 218 years, measured using
`the Rhinoconjunctivitis Quality of Life Questionnaire
`(RQLQ).2! The RQLQ assesses the domains ofactivi-
`ties, sleep, nonnose/noneye symptoms, practical prob-
`lems, nasal symptoms, eye symptoms, and emotions.
`Tolerability was assessed in terms of reported ad-
`verse experiences andvital signs, which included body
`temperature, systolic and diastolic blood pressure,
`and heart and respiration rates, which were measured
`at baseline and at the end of the study.
`
`Statistical Procedures
`This study was designed to detect differences in TNSS
`and onset of action between the 2 active-treatment
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`
`groups. The sample size was based on the results of a
`double-blind, placebo-controlled pilot study in which
`60 patients received 1 week of treatment with azelas-
`tine nasal spray, fluticasone nasal spray, cetirizine
`tablets, or placebo.” In this pilot study, an improve-
`ment in T'NSS of 19.5% was observed with azelastine
`nasal spray, compared with 15.5% with cetirizine. A
`TNSSeffect size of 0.25 (azelastine mean — cetirizine
`mean [pooled SD]) wasidentified for the change from
`baseline to the end of treatment using the same 4-
`pointrating scale as in the present study. Based onthis
`pilot study,
`it was estimated that ~150 patients per
`group would besufficient to detect a difference in ef-
`fect size of 0.25 betweenazelastine nasal spray andce-
`tirizine for the primary efficacy variables with 80%
`powerat the 0.05 level of significance.
`The primary analysis was anintent-to-treat analy-
`sis that includedall randomized patients with 21 post-
`baseline TNSS assessment. Missing TNSSvaluesin this
`population were imputed using the last-observation-
`carried-forward method. The safety analysis included
`all randomizedpatients whoreceived >1 doseof study
`medication and had 21 safety assessment after drug
`administration.
`For the first primary efficacy variable (change in
`TNSSfrom baseline to day 14), the baseline score was
`calculated as the mean of the combined morning and
`evening T'NSS during the placebo lead-in period. The
`change from baseline to day 14 was determined by
`subtracting the mean baseline score from the mean
`TNSSfor the entire 2-week treatment period. Within-
`group comparisons were conducted using a paired t
`test, and between-group comparisons were conducted
`using an analysis-of-variance (ANOVA) model. The
`change from baseline in individual symptom severity
`scores was evaluated using a similar ANOVA model.
`The secondprimary efficacy variable (onset of ac-
`tion) was determined based on the instantaneous
`TNSSover 4 hours. Within each treatmentgroup,time
`to onset was determined using a paired f test on the
`change in TNSS from baseline. Between-group com-
`parisons were made using the same ANOVA model as
`was used for change in TNSSfrom baseline to day 14.
`The change in TNSS from baseline wasalso calcu-
`lated for each day of the study. In assessing effica-
`cy during theinitial 24-hour treatment interval, the
`change in TNSS from baseline to day 2 was calculat-
`ed based on the morning assessment on day 2, with
`baseline defined as the meanof the combined morning
`
`and evening TNSS during the lead-in period. Within-
`and between-group comparisons were performed us-
`ing a paired ¢ test and ANOVA,respectively.
`Changes from baseline to day 14 in the individual
`RQLQ domains and the overall RQLQ score were cal-
`culated and analyzed according to the method described
`by Juniper at al.2! Changesin vital signs were evaluat-
`ed by comparing values before and after treatment.
`All tests of significance were 2-sided. Baseline de-
`mographic and clinical characteristics were summa-
`rized descriptively,
`
`RESULTS
`Patient Disposition and Demographic
`Characteristics
`Three hundred seven patients were randomized to
`receive double-blind treatment, and 299 patients com-
`pleted 2 weeks of treatment (Figure 1). Data for all
`307 patients were included in the safety assessment,
`and data for 306 patients were analyzed for efficacy
`(1 patient in the azelastine nasal spray group had no
`postbaseline diary data and was not included). Four
`patients in the azelastine group and 2 in thecetirizine
`group discontinued the study due to an adverse event,
`and 1 patient in each group wasdiscontinued because
`of a protocol violation. The treatment groups were
`comparable in terms of demographic characteristics
`(Table I). Patients ranged in age from 12 to 74 years
`(mean, 35 years); 62.9% were female and 69.6% were
`white.
`
`Efficacy Analyses
`Change in TNSS from Baseline
`During 2 weeks of treatment, bothazelastine nasal
`spray and cetirizine significantly improved the com-
`bined morning and evening 12-hourreflective TNSS
`compared withbaseline (P < 0.001). At the end of the
`study period, the mean improvement in TNSS was
`5.56 (29.3% improvement) with azelastine nasal
`spray and 4.32 (23.0% improvement) withcetirizine.
`The overall difference in TNSS between the 2 groups
`across both weeks of the study significantly favored
`azelastine nasal spray (P = 0.015)
`(Table Il), The
`improvementin daily symptom scores wassignificant
`for azelastine nasal spray compared with cetirizine
`on study days 8, 9, 10, 12, 13, and 14(all, P < 0.05)
`(Figure 2). A per-protocol analysis that included 145
`patients in the azelastine nasal spray group and 148
`in the cetirizine group for whom complete data were
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`J. Corren et al.
`
`|
`
`Assessedforeligibility
`(N = 398)
`
`| Excluded (n = 91):
`Did not meetinclusion criteria (n = 53)
`Protocol violation (n = 13)
`Adverse event (n = 3)
`Administrative reasons (n = 22)
`
`Randomized
`
`(n = 307)
`
`Allocated to and received
`azelastine nasal spray
`(n = 152)
`
`
`
`Allocated to and received
`cetirizine
`
`(n = 155)
`
`| Discontinued azelastine
`nasal spray:
`Adverse event (n = 4)
`Protocol violation (n= 1)
`
`|
`
`| Discontinued cetirizine:
`Adverse event (n = 2)
`Protocol violation (n= 1)
`
`|
`
`Included in analysis
`(n=152)*
`
`Included in analysis
`(n= 155)
`
`Figure 1. Patient disposition. *One patient had no postbaseline diary data and was not includedin theefficacy |
`analysis. All patients were includedin the safety/tolerability analysis.
`
`available also showeda significant difference in over-
`all improvement in TNSS with azelastine nasal spray
`compared with cetirizine (P = 0.023).
`All individual symptoms on the TNSS weresignifi-
`cantly improved from baseline over the 2-week study
`period with both treatments (P < 0.001). There was a
`statistically significant
`improvement
`in runny nose
`with azelastine nasal spray compared with cetirizine
`(P = 0.003) (Table II).
`
`Onset ofAction
`In the assessment of onset of action over 4 hours,
`the instantaneous TNSS was significantly improved
`from baseline in both treatment groups 15 minutes
`after initial administration (P < 0.001). The difference
`between treatment groups significantly favored azel-
`astine at 60 and 240 minutes (both, P = 0.040) (Figure
`3). At no time point during the 4-hour observationpe-
`
`riod did the improvement in TNSSwith cetirizine ex-
`ceed that with azelastine nasal spray.
`
`Rhinitis Quality of Life Questionnaire
`Scores onall individual domains of the RQLQ and
`the overall RQLQ score were significantly improved
`from baseline in both treatment groups (all, P < 0.001)
`(Table Ill). There were nostatistically significant dif-
`ferences between azelastine nasal spray and cetirizine
`on anyof the individual RQLQ domains. However, the
`overall difference was significant for azelastine nasal
`spray compared with cetirizine (P = 0.049),
`
`Safety Profile
`Both azelastine nasal spray and cetirizine were well
`tolerated. The most commonadverse events with azel-
`astine nasal spray were bitter taste (3.3%), headache
`(2.6%), epistaxis (2.0%), somnolence (1.3%), and nasal
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`Table |. Demographic characteristics of study patients.
`
`|
`
`|
`_ Characteristic
`| Sex, no. (%)
`|
`Female
`Male
`| Age, y
`Mean
`Range
`
`Race, no. (%)*
`White
`Black
`Asian
`Other
`Duration of SAR, y
`Mean
`Range
`
`Azelastine
`Nasal Spray
`(n = 152)
`
`Cetirizine
`(n= 155)
`
`96 (63.2)
`56 (36.8)
`
`94 (60.6)
`61 (39.4)
`
`35.6
`12-74
`
`35.7
`12-74
`
`107 (70.4)
`29 (19.1)
`3 (2.0)
`13 (8.6)
`
`107 (69.0) |
`30 (19.4) |
`6 (3.9)
`12 (7.7)
`
`18.8
`2-51
`
`20.0
`2-58
`
`therefore, was designed
`groups. The present study,
`with a sufficient sample size to detect significant dif-
`ferences in the selected efficacy parameters between
`azelastine nasal spray and cetirizine. The investiga-
`tional sites were distributed throughout the major
`geographic regions of the United States to ensure that
`the study population included a representative sample
`of patients with symptoms of SAR caused by a broad
`spectrum of seasonalallergens.
`During the 2-week treatment period, azelastine
`nasal spray significantly improved the overall TNSS
`compared with cetirizine in patients with moderate
`to severe SAR (P = 0.015). Azelastine nasal spray
`also improved scores for all 4 individual symptoms
`included in the TNSS, with significantly greater im-
`provementin runny nose compared withcetirizine (P =
`0.003). The difference in TNSS between azelastine
`nasal spray and cetirizine became more evident as
`the study progressed, with significant differences in
`TNSS with azelastine nasal spray compared with ce-
`tirizine on study days 8, 9, 10, 12, 13, and 14 (all,
`P < 0.05).
`In the assessment of onset of action, both treatment
`groups hadsignificant improvements from baseline at
`discomfort (1.3%). The most common adverse event
`- 15 minutes (the first time point) after the initial ad-
`with cetirizine was somnolence (2.6%). All other ad-
`ministration of medication and at each subsequent
`verse events were reported in <1%of patients. Four
`time point
`in the 4-hour assessment period (P <
`patients in the azelastine group discontinued the study
`0.001), Based on a comparative studyofcetirizine and
`due to adverse events (1 each, sleeplessness, sinus in-
`fexofenadine that showed nosignificant improvement
`fection, nausea, and allergy exacerbation). One pa-
`in symptoms with cetirizine compared with placebo
`tient in the cetirizine group discontinued the study due
`during the first 2 hours after initial administration,2+
`to somnolence and 1 discontinued due to a skin rash.
`the early onset of activity in the cetirizine group in the
`Noclinically significant abnormalities in vital signs
`present study maybeattributable to the effect of the
`were noted during the study.
`saline nasal spray vehicle. There wasasignificant dif-
`ference with azelastine nasal spray compared with ce-
`tirizine at 60 minutes after initial administration of
`medication and at the last assessment time (240 min-
`utes) (both, P = 0.040), which is consistent with the
`peak effect observed with azelastine nasal spray in
`placebo-controlled studies assessing onset and dura-
`tion of action.25.26
`Patient-reported symptom assessments are the fun-
`damental method for evaluating efficacy in allergy
`clinical trials.*° However,
`in the majority of patients
`withrhinitis, particularly those with SAR, improving
`well-being and quality oflife should be amongthe pri-
`mary goals of treatment.*’ In this study, scores on the
`individual RQLQ domains and the overall RQLQ
`score were significantly improved from baseline in
`
`| SAR = seasonal allergic rhinitis.
`| *Percentages may not equal 100 due to rounding.
`
`DISCUSSION
`It is often asked whetherthere are clinically important
`differences between the antihistamines available for
`the treatmentof allergic rhinitis. Both intranasal and
`oral second-generation antihistamines are recommend-
`ed asfirst-line therapyfor allergic rhinitis*?; however,
`earlier well-controlled comparative clinical trials of
`2 weeks of treatment with oral second-generation an-
`tihistamines have primarily shownsimilarities among
`them.!3.14 Although azelastine nasal spraysignificant-
`ly improved symptoms in patients who remained
`symptomatic after treatment with oral loratadine!® or
`fexofenadine!’ compared with placebo (P < 0.007),
`these studies did not directly compare active-treatment
`
`548
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`

`J. Corren et al.
`
`Table Il. Least squares (LS) mean change and percentage change from baseline in the total nasal symptom score
`(TNSS) and individual symptom scores* (n = 151 azelastine nasal sprayt and n = 155 cetirizine). The |
`treatment groups were comparable at baseline in terms of the TNSSand all individual symptoms.
`
`Symptom/
`| Treatment Group
`
`Baseline,
`LS Mean (SD)*
`
`LS Mean (SD) Change
`from Baseline*
`
`%
`Change
`
`Pvs
`Baselines
`
`Pvs
`Cetirizine*
`
`“TSS
`Azelastine nasal spray
`Cetirizine
`
`Itchy nose
`Azelastine nasal spray
`Cetirizine
`
`Nasal congestion
`Azelastine nasal spray
`Cetirizine
`
`_ Runny nose
`Azelastine nasal spray
`Cetirizine
`
`| Sneezing
`Azelastine nasal spray
`Cetirizine
`
`18.82 (2.86)
`18.50 (2.85)
`
`4.63 (1.14)
`4.64 (0.98)
`
`5.31 (0.62)
`5.27 (0.62)
`
`4.74 (0.97)
`4.61 (0.95)
`
`4.14 (1.25)
`3.98 (1.32)
`
`5.56 (4.68)
`4.32 (4.66)
`
`1.39 (1.45)
`1.09 (1.46)
`
`1.13 (1.16)
`0.96 (1.26)
`
`1.46 (1.39)
`1.00 (1.40)
`
`1.58 (1.49)
`1.29 (1.36)
`
`29,3
`23.0
`
`29.5
`21.7
`
`21.1
`18.1
`
`29.8
`19.6
`
`33.8
`28.2
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0,001
`
`0.015
`
`0.056
`
`0.187
`
`0.003
`
`0.065
`
`| *The TNSSis a combined measureofscares for the severity of itchy nose, nasal congestion, runny nose, and sneezing, rated twice _
`daily (morning and evening) on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe), with a maximum daily score of 24.
`tOne patient had no postbaseline diary data and was not included in the efficacy analysis.
`|
`tAnalysis-of-variance model.
`_
`| SPaired t test.
`
`both treatment groups (all, P < 0.001); however, the
`improvementin overall score wassignificantly greater
`with azelastine nasal spray compared with cetirizine
`(P = 0.049). Improvements in the symptom-related
`domains of the RQLQ were consistent with the im-
`provements in TNSS, and these symptom-related im-
`provements were accompanied by improvements in
`quality-of-life domains relating to function, including
`activities, sleep, practical problems, and emotions.
`The design of the study did not include a placebo
`control group, as both azelastine nasal spray andcetiri-
`zine are proven therapeutic modalities. To maintain
`double-blinding, a double-dummy technique was used
`in which each patient received either an identity-
`concealed bottle of azelastine nasal spray plus placebo
`capsules, or encapsulated cetirizine tablets plus place-
`bo saline nasal spray. The placebo saline nasal spray
`was the same vehicle formulation contained inazelas-
`tine nasal spray. The positive effect of saline nasal
`spray on allergic mediators and symptomshas beenre-
`
`ported in clinical trials in patients with allergic rhini-
`tis?®:2?; therefore, patients randomized to receive cetiri-
`zine were also receiving an “active placebo.” The use
`of an active placebo in the cetirizine group may have
`reduced the difference between the 2 treatment groups;
`in actual practice, where a saline nasal spray is not
`generally used along with an oral antihistamine, the
`difference in effect between azelastine nasal spray and
`cetirizine may be greater than was observed in this
`study. In a previous multicenter study,!” azelastine nasal
`spray at a dosage of 1 spray per nostril twice daily and
`cetirizine 10 mg