ANNALS OF
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`au
`Allergy, Asthma
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`Official Publication of the American College of
`Allergy, Asthma & Immunology
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` Contents of Annals of Allergy, Asthma & .
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`eee
`Immunology Copyright © 2003 by the American
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`EDITOR: Edward-J:-O’ Connell; MD
`Annals of Allergy, Asthma & Immunology
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`GUEST EDITORIAL
`‘he diacnosis of allergy: why is it so Cifficult? ...........cccccssssssssssesesessersenseesssenssnsnssearsnensecestenenes 1
`Robert A. Wood, MD
`
`CME REVIEW ARTICLE
`Primary dietary prevention of food allergy 2.00... eee ees ceceesceeeteeeteeeseenserseeseseeeceseraeeeeneeeneeeas 3
`Alessandro Fiocchi, MD; Alberto Martelli, MD; Anna De Chiara, MD; Guido Moro, MD;
`Amiel Warm, MD and Luigi Terracciano, MD
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`CLINICAL ALLERGY—IMMUNOLOGY ROUNDS
`maerenoult digonosis in & pale Child. ...........0..c.rasrscaccuaresssemnnes somammaaccensne rence <he0 eam 16
`Andrew J. Thompson, MD, MRCPCH;Alastair J.M. Reid, MB, MRCPCH;
`Dara O’Donoghue, MB, MRCPCH; Heather J. Steen, MB, FRCPCH and
`Michael D. Shields, MD, FRCPCH
`A 49-year-old male with intractable dyspnea, wheeze, and COUgN ........:eceseeseeeteeeeeeeeeteeteeeeeees20
`Christopher A. Bates, MD and Lanny J. Rosenwasser, MD
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`ORIGINAL ARTICLES
`Are our impressions ofallergy test performances COrrect?) .........ccsseceseeeeeeteeeeeeeeeeteeesenecaseeeneeney 26
`P. Brock Williams, PhD; Staffan Ahlstedt, PhD; James H. Barnes, PhD;
`Lars Séderstrém, PhD and Jay Portnoy, MD
`Sex differences in asthma, atopy, and airway hyperresponsiveness in a university
`RPTEEAILODL cc.nienenscecnneasansins sansaintoaisasaicarbeiscaKernmuasss cxnMOME ROR AIRINGS cameron ¢umrcninesy oeemeneh ne 34
`Elizabeth S. PausJenssen, MD, FRCPC and Donald W. Cockcroft, MD, FRCPC
`The effect of a steroid “burst” and long-term, inhaled fluticasone propionate on
`Adremal TESCLVE ..ecececccccccscssesecececuceseeeeeseceeeseeeeeeeeeeeeeeeeeeeeseeece ccf ECE; EEE CHEE EE EE EE ULI LUE nn nneneeeneneees 38
`Kim-Lien Nguyen, MD; David Lauver, MD; Isaac Kim, MD and Matthew Aresery, MD
`Fluticasone propionate aqueous nasal spray improves nasal symptomsof seasonalallergic
`Preeewon WSEr Ws. MeSted (PO) ceencceememessmeneamarcocmene vesmmensr serene ever eee44
`Mark S. Dykewicz, MD; Harold B. Kaiser, MD; Robert A. Nathan, MD;
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`ARGENTUM
`ARGENTUM.-
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`A-5
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`000001
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`This material may be protected by Copyright law {Title 17 U.S. Code)
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`
`Efficacy of azelastine nasal spray in patients
`with an unsatisfactory response to loratadine
`William E. Berger, MD, MBA*; Martha V. White, MDT; and the Rhinitis Study Group
`
`
`Objective: To evaluate the effectiveness and safety of azelastine nasal spray, desloratadine, and the combination of azelastine
`nasal spray plus loratadine compared with placebo in patients with seasonal allergic rhinitis who had an unsatisfactory response
`to loratadine.
`Methods: This was a 2-week, multicenter, placebo-controlled, randomized, double-blind study in patients with moderate-to-
`severe symptomsof seasonal allergic rhinitis. Following a 1-week, open-label lead-in period, during which the patients received
`loratadine 10 mg daily, those patients who met the symptom qualification criteria (<25% to 33% improvementtaking loratadine)
`were randomized to treatment with azelastine nasal spray 2 sprays per nostril, twice daily, azelastine nasal spray 2 sprays per
`nostril, twice daily, plus loratadine 10 mg daily, desloratadine 5 mg daily plus placebo (saline) nasal spray, or placebo (saline)
`nasal spray/placebo capsules. The primary efficacy variable was the change from baseline to day 14 in the total nasal symptom
`score, consisting of runny nose, sneezing, itchy nose, and nasal congestion symptom scores recorded twice daily (AM and pM) in
`patient diary cards.
`Results: A total of 428 patients with an unsatisfactory response to loratadine completed the double-blind treatment period.
`After 2 weeks of treatment, azelastine nasal spray (P < 0.001), azelastine nasal spray plus loratadine (P < 0.001), and
`desloratadine (P = 0.039) significantly improved the total nasal symptom score compared with placebo.
`Conclusions: Azelastine nasal spray is an effective treatment for patients with seasonal allergic rhinitis who do not respond
`to loratadine and is an alternative to switching to another oral antihistamine or to using multiple antihistamines.
`Ann Allergy Asthma Immunol. 2003;91:205-211.
`
`INTRODUCTION
`Azelastine nasal spray (Astelin Nasal Spray; MedPointe
`Pharmaceuticals, Somerset, NJ)
`is a topical antihistamine
`formulation indicated for the treatment of seasonal allergic
`rhinitis and nonallergic vasomotor rhinitis. The active ingre-
`dient, azelastine hydrochloride, is a selective, high-affinity,
`histamine H-receptor antagonist with structural and pharma-
`cologic differences that distinguish it from currently available
`antihistamines.'?
`In addition to histamine antagonism, azelastine has dem-
`onstrated inhibitory effects on chemical mediators of the
`inflammatory response over a range of concentrations in
`vitro,
`in animal models of allergy, and in clinical
`trials.
`Azelastine prevented leukotriene generation in mast cells?
`and basophils.’ It also inhibited the synthesis and release of
`leukotrienes in a dose-related manner in cultured eosinophils
`from patients with bronchial asthma.’ In a double-blind, pla-
`cebo-controlled clinical trial,° pretreatment with a single oral
`-dese of azelastine significantly reduced levels of leukotrienes in
`nasal washings from patients with seasonal allergic rhinitis.
`Azelastine demonstrated inhibitory effects on bradykinin-
`induced smooth muscle contraction in isolated tissues! and
`
`* Southern California Research Center, Mission Viejo, California.
`+ Institute for Asthma & Allergy, Wheaton, Maryland.
`£ Rhinitis Study Group membersare listed in Acknowledgments.
`Supported by a grant from Medpointe Pharmaceuticals, Somerset, New
`Jersey.
`Received for publication March 5, 2003.
`Accepted for publication in revised form May 8, 2003.
`
`significantly reduced substance P levels in nasal secretions
`from patients with perennial allergic rhinitis’ and allergic
`asthma.’ Azelastine significantly inhibited the generation of
`interleukins and other cytokines in human lymphocytes’ and
`significantly reduced levels of inflammatory cytokines when
`administered orally and intranasally to patients with allergic
`rhinitis.'!° In addition, in a double-blind, placebo-controlled
`study,'! a single dose of azelastine nasal spray reduced levels
`of eosinophils and neutrophils in nasal washings and de-
`creased levels of eosinophil cationic protein and intercellular
`adhesion molecule-1 expression on nasal epithelial cells in
`patients with seasonalallergic rhinitis.
`In double-blind, placebo-controlled trials in patients with
`seasonal allergic rhinitis,'*!> azelastine nasal spray wasef-
`fective in treating nasal and nonnasal symptomsover 2-week
`study periods. Onset and duration of action assessments in
`patients with seasonalallergic rhinitis showed that azelastine
`nasal spray improved baseline symptom scores within | hour
`in the majority of patients and that
`these improvements
`reachedstatistical significance vs placebo saline spray within
`2 to 3 hours.'*!9 In placebo-controlled, double-blind trials in
`patients with vasomotorrhinitis,'® azelastine nasal spray sig-
`nificantly improved all symptoms of the vasomotor rhinitis
`symptom complex including nasal congestion during 3 weeks
`of treatment.
`Second-generation antihistamines are considered first-line
`therapy for the treatment of seasonalallergic rhinitis'’; how-
`ever, many patients do not experience adequate symptom
`relief with orally administered second-generation agents.'*~*°
`
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`SeenESPEYEFTITERIAHTaA
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`higher and improved by less than 25% to 33% on 3 days
`during the lead-in period (Table 1). One of the 3 TNSS
`qualification scores (either AM and pm) during the lead-in
`period must have been recorded within 3 days of beginning
`the double-blind treatment period on day 1.
`At day —7, patients with a TNSS score of 8 or higher over
`the previous 12 hours and who metthe inclusion/exclusion
`criteria were assigned a patient number and given a 1-week
`supply of loratadine and a diary card in which to record
`symptom severity and the daily use of study medication.
`Patients who did not meet the symptom qualification criteria
`or other study entry criteria on day | or whodid not complete
`the diary as required were discontinued from the study.
`Patients who met the study inclusion/exclusion criteria on
`day 1 and whosatisfied the symptom severity qualification
`criteria were randomized to | of the following 4 treatment
`groups: (1) azelastine nasal spray, 2 sprays per nostril twice
`daily, plus placebo capsule once daily; (2) desloratadine 5 mg
`in capsules, once daily, plus placebo saline nasal spray, 2
`sprays per nostril
`twice daily; (3) azelastine nasal spray, 2
`sprays per nostril
`twice daily, plus loratadine 10 mg in
`capsules once daily; or (4) placebo (saline) nasal spray, 2,
`sprays per nostril
`twice daily, plus placebo capsule once
`daily. Patients were instructed to take 1 capsule each morn-
`ing, 2 sprays per nostril from the nasal spray bottle each
`morning, and 2 sprays pernostril each evening approximately
`12 hours after the morning dose. Capsule medication was
`only taken in the morning. Commercially available loratadine
`and desloratadine were encapsulated to concealtheir identity;
`all medications were blinded in such a mannerthat neither the
`patient nor the investigator was awareof their identity.
`The primary efficacy variable was the change from base-
`line to day 14 in the TNSS, as measured by symptom scores
`recorded twice daily (aM and pM) in patient diary cards. Each
`individual symptom wasscored using a 4-point rating scale:
`0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe.
`Efficacy was evaluated by the change from baseline in the
`12-hour reflective TNSS over 2 weeks of treatment. The
`baseline score was defined as the average of the combined
`morning and evening TNSS during the lead-in period. The
`TNSSfor each patient consisted of the combined scoreofall
`4 symptoms (runny nose, sneezing,
`itchy nose, and nasal
`congestion). Baseline scores were subtracted from the daily
`TNSS to calculate the change from baseline. Change from
`baseline for each active treatment group over the 2-week
`
`Table 1. Symptom Qualification Criteria
`
`Day 7 TNSS qualification
`Minimum baseline TNSS
`score
`
`12
`11
`10
`
`nmoOoo
`
`9 8
`
`Abbreviation: TNSS, total nasal symptom score.
`
`The most common therapeutic options for patients with an
`unsatisfactory response to treatment with oral second-gener-
`ation antihistamines include other oral antihistamines, azelas-
`tine nasal spray, or intranasal steroids. Azelastine nasal spray
`can be used either as monotherapy or in combination therapy
`with oral antihistamines or intranasal steroids; however, the
`effectiveness of azelastine nasal spray in treating patients
`with an unsatisfactory response to oral second-generation
`antihistamines has not been evaluated in a well controlled
`clinical
`trial. The primary objective of this study was to
`evaluate the effectiveness and safety of azelastine nasal
`spray, desloratadine (Clarinex; Schering, Kenilworth, NJ),
`and the combination of azelastine nasal spray plus loratadine
`(Claritin) compared with placebo in patients with seasonal
`allergic rhinitis who had an unsatisfactory responseto treat-
`ment with loratadine.
`
`METHODS
`This was a multicenter, randomized, double-blind, placebo-
`controlled, parallel-group trial conducted at 21 investiga-
`tional sites during the 2002 fall allergy season in patients with
`seasonal allergic rhinitis. The study population consisted of
`male and female patients 12 years of age and older who had
`a minimum 2-year history of seasonalallergic rhinitis and a
`documented positive allergy skin test result during the pre-
`vious year. Patients were excluded from participation for any
`of the following reasons: use of concomitant medications that
`could affect the evaluation of efficacy; any medical or sur-
`gical condition that could affect the metabolism of the study
`medications; having clinically significant nasal disease other
`than seasonal allergic rhinitis or significant nasal structural
`abnormalities; having respiratory infection or other infection
`requiring antibiotic therapy within 2 weeks of beginning the
`baseline screening period; having significant pulmonary dis-
`ease and/or active asthma requiring daily medication; and
`history of or current alcohol or drug abuse. Women of child-
`bearing potential who were not abstinent or practicing an
`accepted method of contraception and women who were
`pregnant or nursing were excluded from participation. All
`concomitant medications were discontinued for protocol-
`specified times, based on the elimination half-life of each
`drug, before beginning the double-blind treatmentperiod. All
`patients or their guardians (if younger than 18 years of age)
`signed an institutional review board-approved informed con-
`sent agreement before participation.
`The study consisted of 2 periods: a 1-week baseline period
`(day —7 to day 1) followed by a 2-week, randomized, double-
`blind treatment period. Patients were seen on an outpatient
`basis on days —7, 1, 7, and 14. Initial baseline qualification
`and assessments occurred on day —7, 1 week before random-
`ization into the double-blind treatment period. Patients qual-
`ified for randomization into the double-blind treatment period
`whentheir total nasal symptom score (TNSS; defined as the
`severity score for individual symptoms of runny nose, sneez-
`ing, itchy nose, and nasal congestion) on day —7 was 8 or
`
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`study period was compared with placebo using a repeated-
`measure analysis of variance according to the restricted max-
`imum likelihood estimation for mixed-effect models. The
`change from baseline in individual symptomseverity scores
`was evaluated using a similar repeated-measure analysis of
`variance model. The primary analysis was an intent-to-treat
`analysis that
`included all patients who were randomized.
`Missing TNSS values in the intent-to-treat population were
`imputed using the last observation carried forward method.
`The safety analysis included all randomized patients who re-
`ceived at least 1 dose of study medication and had at least
`|
`safety evaluation after drug administration. The incidence of
`adverse experiences was summarized for each treatment group.
`Based on the change from baseline in TNSS in previous
`studies with azelastine nasal spray and assuming a 0.05 level
`of significance, 80% power, and an average difference reduc-
`tion of 1.0 unit in TNSS with SD of 2.5, a sample size of
`approximately 100 patients per treatment group was required.
`All inferential statistics were calculated at the 0.05 level of
`significance.
`
`RESULTS
`
`Patient Disposition
`A total of 596 patients were screened for participation in the
`trial; 440 patients met the study entrance criteria and were
`randomized to double-blind treatment. Of the 156 patients
`whodid not qualify for randomization, 104 failed to meet the
`inclusion/exclusion criteria at day —7, and 52 did not meet
`the minimum symptom score criteria at day 1. A total of 428
`of the 440 randomized patients completed the 2-week double-
`blind treatment period. Of the 12 patients who did not com-
`plete the study, 4 discontinued due to an adverse event and 8
`discontinued for administrative or other reasons.
`
`Demographic and Pretreatment Characteristics
`The 4 treatment groups were comparable with regard to
`demographic characteristics and baseline TNSS, and there
`
`were nostatistically significant changes in TNSS within the
`treatment groups or statistically significant differences in
`TNSS between treatment groups during the lead-in period.
`The patients ranged in age from 12 to 79 years old with a
`mean age of approximately 35 years. Sixty-six percent of the
`patients were female, 80% were white, 11% were black, and
`9% were Asian or other racial background (Table 2). During
`the 12-month period before enrollment in the study, 49% of
`the patients had used over-the-counter antihistamines, 30%
`had been treated with fexofenadine, 28% had been treated
`with loratadine, 17% had been treated with desloratadine, and
`4% had been treated with azelastine nasal spray. In addition,
`43% of the patients had been treated with 2 or more antihis-
`tamines during the 12 months before enrollment.
`
`Efficacy
`After 2 weeksof treatment, the mean percentage change from
`baseline in the overall TNSS was 21.9% with azelastine nasal
`spray (P < 0.001 vs placebo), 21.5% with azelastine nasal
`spray plus loratadine (P < 0.001 vs placebo), 17.5% with
`desloratadine (P = 0.039 vs placebo), and 11.1% with pla-
`cebo (Table 3 and Fig 1). The mean absolute improvements
`from baseline and the relative contribution of the individual
`symptoms to the TNSS are shown in Figure 2.
`Patients treated with azelastine nasal spray monotherapy
`had statistically significant improvements vs placebo for rhi-
`norrhea (21.6% vs 11.0%; P = 0.004), sneezing (26.1% vs
`7.0%; P < 0.001), and itchy nose (23.4% vs 12.4%; P =
`0.001). Improvements in individual rhinitis symptoms in the
`azelastine nasal spray plus loratadine treatment group were
`virtually identical to the improvements seen with azelastine
`nasal spray monotherapy, with statistically significant differ-
`ences for rhinorrhea (P = 0.011), sneezing (P < 0.001), and
`itchy nose (P < 0.001). In the desloratadine group, the only
`individual symptom that was significantly improved over
`placebo was sneezing (P = 0.009).
`
`Table 2. Demographic Characteristics
`
`Characteristic
`
`Azelastine nasal
`Azelastine nasal
`spray plus
`Desloratadine
`Placebo (n = 111)
`spray (n = 108)
`loratadine
`(n = 111)
`
`(n = 110)
`
`N
`%
`N
`%
`N
`%
`N
`
`Sex
`Male
`Female
`Race
`Caucasian
`African-American
`Asian
`Other
`
`43
`65
`
`87
`14
`3
`4
`
`39.8
`60.2
`
`80.6
`13.0
`2.8
`3.7
`
`36
`74
`
`89
`10
`2
`9
`
`32.7
`67.3
`
`80.9
`9.1
`1.8
`8.2
`
`37
`74
`
`84
`15
`1
`11
`
`33.3
`66.7
`
`75.7
`13.5
`0.9
`9.9
`
`34
`77
`
`91
`14
`1
`8
`
`%
`
`30.6
`69.4
`
`82.0
`9.9
`0.9
`7.2
`
`Age (years)
`36.9
`32.6
`35.4
`35.9
`Mean(SD)
`
`
`
`
`12 to 70 15 to 59 12 to 73Range 12 to 79
`
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`SSSRaEaHRTITLTAaSAPPBATSceRA|
`
`Table 3. Change from Baseline in Mean am and pm Total Nasal Symptom Scores and Individual Symptom Scores
`Azelastine nasal spray
`Azelastine nasal spray plus
`Placebo (n = 110)*
`Desloratadine (n = 111)
`(n = 106)*
`loratadine (mn = 108)*
`
`.
`—
`_
`=
`=
`—
`Mean
`P
`%
`Mean
`Mean
`P
`%
`Mean
`Mean
`%o
`Mean
`P
`%
`Mean
`Mean
`baseline improv.
`Improv. valuet baseline improv.
`Improv. valuet baseline improv.
`Improv. valuet baseline improv.
`Improv.
`
`
`Symptoms
`
`TNSS
`AM
`PM
`Rhinorrhea
`AM
`PM
`Sneezing
`AM
`PM
`Itchy nose
`AM
`PM
`Congestion
`AM
`PM
`
`17.70
`8.93
`8.78
`4.63
`2.33
`2.30
`3.60
`1.81
`1.80
`4.40
`2.20
`2.20
`5.07
`2.59
`2.48
`
`3.88
`1.87
`2.02
`1.00
`0.46
`0.53
`0.94
`0.48
`0.47
`1.03
`0.48
`0.55
`0.90
`0.44
`0.46
`
`21.9
`20.9
`23.0
`21.6
`19.7
`23.0
`26.1
`26.5
`26.1
`23.4
`21.8
`25.0
`17.8
`17.0
`18.5
`
`<0.001
`0.003
`<0.001
`0.004
`0.019
`0.002
`<0.001
`<0.001
`<0.001
`0.001
`0.022
`<0.001
`0.151
`0.145
`0.190
`
`18.04
`9.15
`8.88
`4.61
`2.37
`2.24
`3.79
`1.86
`1.92
`4.47
`2.25
`2.22
`5.15
`2.66
`2.50
`
`3.88
`1.91
`1.96
`0.93
`0.47
`0.45
`0.94
`0.45
`0.49
`1.05
`0.51
`0.53
`0.95
`0.48
`0.48
`
`21.5
`20.9
`22.1
`20.2
`19.8
`20.1
`24.8
`24.2
`25.5
`23.5
`22.7
`23.9
`18.4
`18.0
`19.2
`
`<0.001
`0.002
`0.001
`0.011
`0.014
`0.022
`<0.001
`0.001
`<0.001
`<0.001
`0.008
`<0.001
`0.080
`0.056
`0.133
`
`17.67
`8.96
`8.72
`4.66
`2.37
`2.29
`3.57
`1.78
`1.80
`4.31
`2.20
`2.12
`5.12
`2.61
`2.51
`
`3.10
`1.50
`1.60
`0.78
`0.36
`0.41
`0.71
`0.37
`0.35
`0.78
`0.40
`0.39
`0.82
`0.37
`0.45
`
`17.5
`16.7
`18.3
`16.7
`15.2
`17.9
`19.9
`20.8
`19.4
`18.1
`18.2
`18.4
`16.0
`14.2
`17.9
`
`0.039
`0.081
`0.031
`0.087
`0.195
`0.064
`0.009
`0.014
`0.014
`0.084
`0.167
`0.079
`0.326
`0.505
`0.243
`
`16.79
`8.54
`8.27
`4.36
`2.24
`2.13
`3.43
`1.70
`1.74
`4.02
`2.04
`1.99
`4,98
`2.57
`2.44
`
`1.87
`0.98
`0.92
`0.48
`0.25
`0.24
`0.24
`0.14
`0.11
`0.50
`0.28
`0.24
`0.67
`0.32
`0.35
`
`11.4
`11.5
`14.4
`11.0
`11.2
`11.3
`7.0
`8.2
`6.3
`12.4
`13.7
`12.1
`13.5
`12.5
`14.5
`
`Abbreviation: TNSS,total nasal symptom score.
`* Two patientsin the azelastine nasal spray group, 2 patientsin the azelastine nasal spray plus loratadine group, and 1 patient in the placebo group had no postbaseline
`diary data and were not included in the efficacy analysis.
`+ Statistical significance vs placebo.
`
`LO)gaii
`
`
`
`
`
`PercentImprovementfromBaseline
`
`30°
`
`@ Azelastine Nasal Spray + Placebo Capsule
`© Azelastine Nasal Spray + loratadine
`desloratadine + Placebo Saline Nasal Spray
`[1 Placebo Capsule + Placebo Saline Nasail Spray
`
`|
`
` Rhinorrhea
`
`Figure 1. Mean percent improvement from base-
`line in total nasal symptom score (TNSS) and indi-
`vidual symptom scores.
`
`Sneezing
`
`itchy Nose
`
`Congestion
`
`™ P< 01 vs. placebo
`|” Ps.05 vs. placebo |
`
`Safety
`Bitter taste was the most commonly reported adverse expe-
`rience among patients treated with azelastine nasal spray
`monotherapy (11%) and azelastine nasal spray plus loratadine
`(4%). Headache (3%) and pharyngitis (4%) were the most
`commonly reported adverse events with desloratadine,
`whereas headache (7%) was the most commonly reported
`adverse event in the placebo group. Somnolence was reported
`by 2% of the patients treated with azelastine nasal spray
`
`compared with 1% for patients treated with azelastine nasal
`spray plus loratadine, 1% for patients treated with deslorata-
`dine, and 1% for patients treated with placebo.
`Twopatients treated with azelastine nasal spray mono-
`therapy discontinued the study due to an adverse event: one
`patient had moderate chest pain and the other experienced
`lightheadedness. One patient
`in the desloratadine group
`(headache and nausea) and | patient in the placebo group
`(rash) also discontinued due to an adverse event. None of these
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`@ Azelastine Nasal Spray + Placebo Capsule
`
`0 Azelastine Nasal Spray + loratadine
`
`{2 desloratadine + Placebo Saline Nasal Spray
`
`0 Placebo Capsule + Placebo Saline Nasal
`
`
`
`
`
` Spray
`
`
`
`Figure 2. Mean absolute improvement from base-
`line in total nasal symptom score (TNSS)and indi-
`vidual symptom scores.
`
`ho
`
`
`
`
`
`
`
`MeanAbsoluteImprovementfromBaseline
`
`TNSS
`
`Rhinorrhea
`
`Sneezing
`
`Itchy Nose
`
`Congestion
`
`P< 01 vs. placebo
`* P<_05 vs. placebo
`
`events were consideredserious, and all of the patients recovered
`fully upon discontinuation of the study medications.
`
`DISCUSSION
`This double-blind, placebo-controlled study demonstrated
`that azelastine nasal spray was an effective therapy for sea-
`sonal allergic rhinitis patients who had an unsatisfactory
`response to loratadine. The patients enrolled in this study had
`moderate-to-severe rhinitis symptoms that improved by less
`than 25% to 33% compared with their baseline symptom
`scores whentreated with loratadine for 7 days. After 2 weeks
`of treatment, patients in the azelastine nasal spray group had
`a statistically significant (P < 0.001) mean improvementin
`the TNSS that was approximately twofold greater than the
`improvement
`in the placebo group. Patients treated with
`azelastine nasal spray in combination with loratadine also had
`statistically significant
`(P < 0.001)
`improvement
`in the
`TNSS compared with placebo; however,
`this combination
`regimen resulted in the same improvement as seen with
`azelastine nasal spray alone. Patients treated with deslorata-
`dine hadstatistically significant (P = 0.039) improvement vs
`placebo in the TNSS, although the magnitude of improve-
`ment was approximately 40% less than that seen with azelas-
`tine nasal spray.
`in the TNSS with azelastine
`The overall
`improvement
`nasal spray monotherapy was the result of statistically sig-
`nificant improvements over placebo in 3 of the 4 individual
`symptoms making up the TNSS. The combination of azelas-
`tine nasal spray with loratadine resulted in the same degree of
`improvement
`for each individual symptom as seen with
`azelastine nasal spray alone, which suggests that the improve-
`ments in rhinitis symptoms with this combination therapy
`regimen were attributable to azelastine nasal spray. In con-
`
`trast, the overall improvement in the TNSS with deslorata-
`dine was primarily due to the effect on sneezing, the only
`individual symptom for which desloratadine demonstrated a
`significant improvement over placebo.
`Although nasal congestion was not significantly improved
`in the active treatment groups, well controlled studies have
`shownthat both azelastine nasal spray and desloratadine can
`improve nasal congestion in patients with rhinitis. For azelas-
`tine nasal spray, statistically significant
`improvements in
`nasal congestion have been reported in patients with seasonal
`allergic rhinitis’ and nonallergic vasomotor rhinitis!® and
`have been demonstrated objectively by anterior rhinomanom-
`etry in patients with seasonalallergic rhinitis.?' Desloratadine
`was shown to significantly improve nasal congestion in pa-
`tients with allergic rhinitis and asthma” and to improve nasal
`inspiratory flow rates in patients with seasonal allergic rhi-
`nitis.”> In the current study, the improvement in the placebo
`group for the individual symptomsof the TNSS wasgreatest
`for nasal congestion, and the failure to detect statistically
`significant differences between active treatments and placebo
`may be due to the nasal irrigation provided by the placebo
`saline nasal spray. In future studies,
`it would be useful to
`include objective measurements of nasal airflow to more
`accurately determine the effect of second-generation antihis-
`tamines on nasal congestion.
`As expected, the incidence of adverse experiences was low
`in the 3 active treatment arms of this study. Bitter taste (11%)
`of the medication was the most commonly reported adverse
`event with azelastine nasal spray. The incidence of somno-
`lence with azelastine (2%) was similar to that with deslora-
`tadine (1%), a nonsedating antihistamine, and placebo (1%).
`Although azelastine is not considered a nonsedating antihis-
`tamine, studies using positron emission tomography to ana-
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`lyze histamine receptor binding in the human brain demon-
`strated that
`the degree of penetration of the blood-brain
`barrier and the extent of histamine receptor occupancy with
`azelastine was significantly less than that of first-generation
`antihistamines and comparable with that of nonsedating sec-
`ond-generation antihistamines.”
`Theselection of patients with an inadequate response to an
`oral antihistamine for inclusion in this study addresses a
`commontreatment outcomein patients with allergic rhinitis.
`Antihistamines are consideredfirst-line therapy for allergic
`rhinitis; however, many patients treated with oral second-
`generation antihistamines do not achieve an optimal thera-
`peutic response and are often treated with other antihista-
`mines or
`intranasal
`steroids either alone or
`in various
`combination regimens. In a study of 1,458 secondary school
`students with allergic rhinitis,'!® 73% of the students reported
`using 2 or more rhinitis medications, whereas only 27%
`reported using monotherapy. In a study of drug utilization
`patterns in more than 60,000 patients initiating treatment for
`seasonal allergic rhinitis, nearly one third of the patients
`either added or switched drugs during the study period, which
`resulted in a threefold and twofold increase, respectively, in
`the numberofprescriptions for these patients compared with
`patients treated with monotherapy.'? In addition, a survey
`conducted by the American College of Allergy, Asthma, and
`Immunology reported that 52%of allergists and 39%of
`primary care physicians surveyed prescribed morethan | oral
`antihistamine, and more than 75% of allergists and primary
`care physicians cited inadequate symptom relief as the reason
`for switching medications or using combination therapy reg-
`imens.”° Consistent with these findings, 43%of the patients in
`the current study had used 2 or more antihistamines during
`the 12 months before enrollment in the double-blindtreat-
`ment period.
`
`CONCLUSION
`This study demonstrated that azelastine nasal spray was an
`effective treatment for patients with seasonalallergic rhinitis
`who had an unsatisfactory responseto loratadine. In addition,
`compared with treatment with azelastine nasal spray mono-
`therapy, no additional therapeutic benefit was achieved by
`adding loratadine in combination therapy with azelastine
`nasal spray. For rhinitis patients who experience limited
`clinical improvement with oral antihistamines, azelastine na-
`sal spray is an alternative to switching to another oral anti-
`histamine or to using multiple antihistamines.
`
`ACKNOWLEDGMENTS
`The authors thank William J. Wheeler, PhD for contributions
`to the design of the study and assistance in preparation of the
`manuscript.
`+ Members of the Rhinitis Study Group are: Dean Atkin-
`son, MD, Oklahoma City, OK; Charles Banov, MD, Charles-
`ton, SC; David Bernstein, MD, Cincinnati, OH; Jimmy Chev-
`alier, MD, Glendale, AZ; David Cook, MD, Danville, CA;
`Jonathan Corren, MD, Los Angeles, CA; Albert Finn, MD,
`
`Charleston, SC; David Gossage, MD, Knoxville, TN; Frank
`Hampel, MD, New Braunfels, TX; Melvin Haysman, MD,
`Savannah, GA; Craig LaForee, MD, Raleigh, NC; Dennis
`Ledford, MD, Tampa, FL; William Lumry, MD,Dallas, TX:
`Jonathan Matz, MD, Baltimore, MD; John Morris, MD, Lou-
`isville, KY; Paul Ratner, MD, San Antonio, TX; Eric Schen-
`kel, MD, Easton, PA; Julius Van Bavel, MD, Austin, TX; and
`Michael Welch, MD, San Diego, CA.
`
`REFERENCES
`I. Inoue Y. Basic studies on antiallergy drug. 4-(p-chlorobenzyl)-
`2{N-methylperhydroazepinyl-(4)]-1-(2H)-phthalazinone hydro-
`chloride (azelastine). Nichi Idaishi. 1983;50:65-72.
`2. Zechel HJ, Brock N, Lenke D, Achterrath-Tuckermann U. Phar-
`macological and toxicological properties of azelastine, a novel
`antiallergic agent. Arzneimittelforschung. 1981;31:1184-1193.
`3. Chand N, Pillar J, Nolan K, Diamantis W, Sofia RD. Inhibition
`ofallergic and nonallergic leukotriene C, formation andhista-
`minesecretion by azelastine: implication for its mechanism of
`action. Int Arch Allergy Appl Immunol. 1989;90:67—70.
`4, Hamasaki Y, Shafigeh M, Yamamoto S, etal. Inhibition of
`leukotriene synthesis by azelastine. Ann Allergy Asthma Immu-
`nol. 1996;76:469—-475.
`5. Matsumura M, Matsumoto Y, Takahashi H, et al. Inhibitory
`effects of azelastine on leukotriene By, C,, and D, release and
`production by bronchial asthmatic eosinophils. Respir Res.
`1990;9:206 -212.
`6. Shin MH, Baroody F, Proud D, Kagey-Sobotka A, Lichtenstein
`LM, Naclerio RM. Theeffect of azelastine on the early allergic
`response. Clin Exp Allergy. 1992;22:289-295.
`7. Shinoda M, Watanabe N, Suko T, Mogi G, Takeyama M.
`Effects of antiallergic drugs on substance P (SP) and vasoactive
`intestinal peptide (VIP)in nasal secretions. Am J Rhinol. 1997,
`11:237-241.
`8. Nieber K, Baumgarten C, Rathsack R,et al. Effect of azelastine
`on substance P content in bronchoalveolar and nasal
`lavage
`fluids of patients with allergic asthma. Clin Exp Allergy. 1993;
`23:69-71.
`9. Ueta E, Osaki T, Yoneda K, Yamamoto T. Contrasting influ-
`ence of peplomycin and azelastine hydrochloride (Azeptin) on
`reactive oxygen generation in polymorphonuclear leukocytes,
`cytokine generation in lymphocytes, and collagen synthesis in
`fibroblasts. Cancer Chemother Pharmacol. 1995,35:230-236.
`10. Ito H, Nakamura Y, Takagi S, Sakai K. Effects of azelastine on
`the level of serum interleukin-4 and soluble CD23antigen in the
`treatment of nasal allergy. Arzneimittelforschung. 1998;48:
`1143-1147.
`11. Ciprandi G, Pronzato C, Passalacqua G,etal. Topical azelastine
`reduces eosinophil activation and intercellular adhesion mole-
`cule-1 expression on nasal epithelial cells: an antiallergic activ-
`ity. J Allergy Clin Immunol. 1996;98: 1088-1096.
`12. Ratner PH, Findlay SR, Hampel F, van Bavel J, Widlitz MD,
`Freitag JJ. A double-blind, controlled trial to assess the safety
`and efficacy of azelastine nasal spray in seasonal allergic rhi-
`nitis. J Allergy Clin Immumol. 1994;94:818-825.
`13. Storms WW,Pearlman DS, ChervinskyP,et al. Effectiveness of
`azelastine nasal solution in seaso