ANNALS OF
`
`Allergy, Asthma
`& Immunology
`
`Official Publication of the American College of
`
`Allergy, Asthma & Immunology Contents of Annals of Allergy, Asthma &
`
`Cover Photo/Lombardy Poplar
`
`Popreluy-nigra
`Sensitization to poplar pollen has been found in
`allergic asthmatics, ...”
`ee
`(refer to Rage|A6)
`
`Immunology Copyright © 2006 by the American
`College of Allergy, Asthma & Immunology.
`EDITOR: Gailen D> Marshall;MD; PhD
`Annals of Allergy, Asthma & Immunology
`University of Mississippr Medical Center
`2500 North State Street
`Jackson;MS-39216
`(601) 815-5527
`enon bee
`mo
`=a
`pa
`gmarshall@ medicine-umsmed:edu
`
`VOLUME97, SEPTEMBER, 2006
`
`tt
`
`sem
`
`IN MEMORIAM
`John C. Selner, MD, February 5, 1936, to July 20, 2006 .ooceccccccecccceceseessesscsetsecsesseeseaseaes 269
`Gailen Marshall, MD, PhD
`
`GUEST EDITORIAL
`
`
`Specific polysaccharide antibody deficiency .....c.ceceeeccccecsceeseeeseesescesceseesecseesessessesseessessssessceueess 271
`Charles H. Kirkpatrick, MD
`
`CME REVIEW ARTICLE
`Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal
`MMECEOLYSIS ......ccsccesegssessecesseoeenereesnenssennersanenteneaesqnsepennssnsesnsensees dassnvasueasasuuratia taatrasvase seaeaseareesensatee 272
`Barzin Khalili, MD, and Sami L. Bahna, MD, DrPH
`
`CASE REPORTS
`Lack of cross-reactivity between 5-aminosalicylic acid-based drugs: a case report and review
`MEME HCCTAUULS 2... cocvssssscsoerssnsecsesseasessanecssaneusnsenerserersserstaneseerecaneenseprsecaeenteareeaneneassereeuarnaneateatsle 284
`Shiang-Ju Kung, MD; Cuckoo Choudhary, MD; Stephen J. McGeady, MD and
`John R. Cohn, MD
`Improvement of asthma control with omalizumab in 2 obese pediatric asthmapatients........ 288
`Kenny ¥. C. Kwong, MD, and Craig A. Jones, MD
`Clustered sensitivity to fungi: anaphylactic reactions caused by ingestive allergy
`BOBCASUS 1) cccvsenveves sansuanwasssanassuwas saaverusens sseeuwitadi aa ssceeeednednedsetunani coasbadessisedsatshcnseassesenssescsecemnreps) Eee 294
`Kristiina Airola, MD, PhD; Leena Petman and Soili Méikinen-Kiljunen, PhD
`
`REVIEW
`Use of the Health Plan Employer Data and Information Set for measuring and
`improving the quality Of asthma Care ooo... ceeececccesscessccesceeseecesseeseeeeseceseecsuesssuseesecsscseecsueceas 298
`Erwin W. Gelfand, MD; Gene L. Colice, MD; Leonard Fromer, MD, FAAFP;
`William B. Bunn Il, MD, JD, MPH and ThomasJ. Davies, JD, MPA
`
`Exhibit beee |
`Exhibit 1162
`(Continued on page A7)
`IPR2017-00807
`000001
`IPR2017-00807
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`ARGENTUM
`to ARGENTUM
`AS
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`000001
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`——_——SoCeeee"_a_—_—_
`Jmpact of azelastine nasal spray on symptoms
`and quality of life compared with cetirizine oral
`tablets in patients with seasonal allergic rhinitis
`william Perger, MD*; Frank Hampel, Jr, MD7+; Jonathan Bernstein, MD+; Shailen Shah, MD§;
`garry Sacks; MD; and Eli O. Meltzer, MD]
`
`
`
`Background: In fall 2004, the first Azelastine Cetirizine Trial demonstrated statistically significant improvementsin thetotal
`pasal symptom score (TNSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores with the use of azelastine
`nasal spray vs oral cetirizine in patients with seasonalallergic rhinitis (SAR).
`Objective: To compare the effects of azelastine nasal spray vscetirizine on the TNSS and RQLQscoresin patients with SAR.
`Methods: This 2-week, double-blind, multicenter trial randomized 360 patients with moderate-to-severe SAR to azelastine,
`2 sprays per nostril twice daily, or cetirizine, 10-mg tablets once daily. The primary efficacy variable was the 12-hourreflective
`JNSS (rhinorrhea, sneezing, itchy nose, and nasal congestion). Secondary efficacy variables were individual symptom scores and
`the RQLQ score.
`Results: Azelastine nasal spray and cetirizine significantly improved the TNSS and individual symptoms compared with
`baseline (P < .001). The TNSS improved by a mean of 4.6 (23.9%) with azelastine nasal spray compared with 3.9 (19.6%) with
`cetirizine. Significant differences favoring azelastine nasal spray were seen for the individual symptoms of sneezing and nasal
`congestion. Improvements in the RQLQ overall (P = .002) and individual domain (P = .02) scores were greater with azelastine
`nasal spray. Both treatments were well tolerated.
`Conclusions: Azelastine nasal spray and cetirizine effectively treated nasal symptoms in patients with SAR. Improvementsin
`the TNSS and individual symptomsfavored azelastine over cetirizine, with significant differences for nasal congestion and
`sneezing. Azelastine nasal spray significantly improved the RQLQ overall and domain scores compared with cetirizine.
`AnnAllergy Asthma Immunol. 2006;97:375-381.
`
`_
`
`INTRODUCTION
`Allergic rhinitis (AR) is one of the most commondiseases in
`the genera! population. It is estimated that AR affects more
`than 50 million people in the United States, which represents
`_ approximately 20% of the general population.'” The various
`forms of nonallergic rhinitis have been reported to affect 15
`(020 million persons in the United States.’ In addition to AR
`‘ad nonallergic rhinitis, estimates suggest that 22 million to
`26 million persons have mixed rhinitis,
`ie, seasonal AR
`ee) wiih exacerbations from exposure to nonallergic trig-
`gers,*9
`Azelastine nasal spray is a topically administered second-
`generation antihistamine indicated for the treatment of SAR
`, id nonallergic vasomotorrhinitis. Azelastine is a phthalazi-
`fone derivative and represents a unique class of antihista-
`_ Mines. The primary mechanism of action of azelastine is
`
`—
`{ “Southern California Research, Mission Viejo, California.
`‘Central Texas Health Research, New Braunfels, Texas.
`| *Bemstein Clinical Research Center, Cincinnati, Ohio.
`‘Allergy and Asthma Consultants of NJ-PA PC, Collegeville, Pennsylvania.
`iMedPointe Pharmaceuticals, Somerset, New Jersey.
`| oe & Asthma Medical Group & Research Center APC, San Diego,
`Oomia,
`inding for this study was provided by MedPointe Pharmaceuticals.
`“tived for publication September 28, 2005.
`“epted for publication in revised form February 13, 2006.
`
`b
`
`H,-receptor antagonism. Azelastine also has demonstrated
`inhibitory effects on other mediators of inflammation, includ-
`ing leukotrienes,° bradykinin and substance P,°’ cytokines,®
`intercellular adhesion molecule 1 expression,’ and eosinophil
`chemotaxis.’ Cetirizine hydrochloride is an oral second-gen-
`eration antihistamine indicated for the treatment of SAR and
`perennial AR. Cetirizine also has demonstrated inhibitory
`effects on leukotrienes,'° prostaglandins," intercellular adhe-
`sion molecule | expression,'? and eosinophil chemotaxis. !*
`In fall 2004, the effectiveness and tolerability of azelastine,
`2 sprays per nostril twice daily, were compared with those of
`cetirizine, 10-mg tablets once daily, in a multicenter study of
`307 patients with moderate-to-severe SAR (the first Azelas-
`tine Cetirizine Trial [ACT I]).' During the 2-week double-
`blind treatment period, azelastine nasal spray significantly
`improved the overall total nasal symptom score (TNSS) com-
`pared with cetirizine (P = .02). Azelastine nasal spray also
`improved all 4 symptoms of the TNSS compared with base-
`line, with significantly greater improvementvs cetirizine for
`rhinorrhea (P = .003) and differences that trended toward
`significance for itchy nose (P = .06) and sneezing (P = .07).
`Differences in the TNSS between azelastine nasal spray
`and cetirizine were more evident as the study progressed,
`with statistically significant differences favoring azelastine
`nasal spray on study days 8 through 14. In addition, azelastine
`nasal spray significantly improved health-related quality of
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`STNTDLERANTTTATARaweRTay
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`life (QoL) based on the Rhinoconjunctivitis Quality of Life
`Questionnaire (RQLQ) compared with cetirizine (P = .049).
`These significant improvements over cetirizine in symptom
`scores and QoL variables were observed even though both
`treatments were highly effective compared with the baseline
`TNSS and RQLQ scores (P < .001).
`Outcomesin clinical trials in rhinitis can include symptom
`assessments, airway patency, and nasal cytology, and all are
`useful in evaluating the effectiveness of pharmacologic inter-
`ventions. However, effective treatment of the rhinitic patient
`also includes improving physical, psychological, and emo-
`tional factors that may adversely affect the patient’s ability to
`function in daily activities.? It is becoming increasingly evi-
`dent that a more comprehensive measure of health status in
`patients with AR requires that health-related QoL assess-
`ments are made in conjunction with clinical assessments of
`symptoms.'* The objective of this study was to confirm the
`results of the ACT I by comparing the effects of using
`azelastine nasal spray vs cetirizine oral tablets on the TNSS
`and RQLQ scores according to an identical study design in
`patients with moderate-to-severe SAR.
`
`METHODS
`
`Patients
`Qualified patients were males and females 12 years and older
`with at least a 2-year history of SAR and a documented
`positive skin test reaction to ambient pollen aeroallergen
`during the previous year. Exclusion criteria were use of
`concomitant medication(s) that could affect the evaluation of
`efficacy; any medical or surgical condition that could affect
`the metabolism of the study medications; clinically signifi-
`cant nasal disease (other than SAR) or significant nasal
`structural abnormalities; respiratory tract
`infection or other
`infection requiring antibiotic drug therapy within 2 weeks of
`beginning the baseline screening period; a history of or cur-
`rent alcohol or other drug abuse; or significant pulmonary
`disease, including persistent asthma requiring daily controller
`medication. Women of childbearing potential not using an
`accepted method of contraception and women who were
`pregnant or nursing also were excluded from participation.
`The use of allergy medications was discontinued before be-
`ginning the open-label lead-in period; use of oral antihista-
`mines was discontinued for a minimum of5 days and intra-
`nasal corticosteroids for a minimum of 14 days.
`
`Study Design
`This 2-week, randomized, double-blind, parallel-group com-
`parative trial (ACT II) was conducted during the 2005 spring
`allergy season at 24 investigational research centers distrib-
`uted throughout the major geographic regions of the United
`States. The study was approved by Sterling Institutional Re-
`view Board (Atlanta, GA), andall the patients or their guard-
`ians (for patients <18 years old) signed the institutional
`review board—approved informed consent agreement before
`participation.
`
`Azelastine nasal spray (Astelin; MedPointe Pharmacey}
`cals, Somerset, NJ) was supplied in polyethylene bot,
`containing 30 mL of study medication. The 10-mg cetirizip, }
`tablets (Zyrtec; Pfizer Inc, New York, NY) were enclose it
`a placebo-matching capsule overfilled with lactose. Placeby }
`nasal spray was provided in polyethylene bottles containiny
`30 mL ofvehicle solution. Placebo capsules werefilled With }
`lactose. Each patient received either (1) active azeiasting, )
`sprays per nostril twice daily,
`in the morning andevening,
`and a placebo capsule once daily in the morningor (2)acti
`cetirizine once daily in the morning and placebo na:al spray
`2 sprays pernostril twice daily, in the morning andevening’
`to ensure adequate blinding of the study. The dissolutionrate
`of 10-mg cetirizine tablets and 10-mg encapsulated cetirizige ?
`tablets overfilled with lactose were shown to be almostidep-
`tical at the 20- and 30-minute (100% dissolution) points a?
`37°C in a comparative dissolution assay performed by
`McKesson Bioservices (Rockville, MD) (MedPointe Pharma. +
`ceuticals, data on file).
`Patients who met the inclusion and exclusioncriteria wer +
`randomized to treatment groups by means of a computer
`generated randomization schedule. The randomization sched-,
`ule was provided by the biostatistical group (13 Statprobe,
`Ann Arbor, MI) employed by the sponsor, and accesstothe ,
`random code was confidential and accessible only to autho
`rized persons who were notinvolved in the study. E lindingo
`the study was preservedat each studysite until all the patients
`|
`completed the study and the database was locked.
`The study began with a 1-week, single-blind, placebo’
`lead-in period, during which patients received placebo nasil
`spray and placebo capsules and recorded their 12-hourreflec |
`tive rhinitis symptom severity scores twice daily (morning
`and evening) in diary cards to determinetheir eligibility for?
`entry into the double-blind treatment period. Symptom sever
`ity was determined by the TNSS, which consisted of runt) }
`nose, sneezing, nasal
`itching, and nasal congest on scored
`twice daily (morning and evening) on a severity scale from) ,
`to 3 (0 = none,
`1 = mild, 2 = moderate, and 3 = severe},
`such that the maximum possible daily TNSS was 24. Patient’ ,
`qualified for entry into the lead-in periodif they had a TNSS
`of at least 8 and a nasal congestion score of at leest 2 during ,
`the previous 12 hours and metall the study inclusion and
`exclusion criteria. To be eligible for entry into tie double
`blind treatmentperiod, patients must have recorded either ®
`morning or evening TNSS of at least 8 on at least 3 days
`during the lead-in period and a morning or even'1g conges|
`tion score of 3 on at
`least 3 days. For TNSS and nasi I
`congestion,
`| of the 3 days selected must have occunns® *
`within 2 days of study day 1.
`-
`
`Efficacy and Safety Variables
`The primary efficacy variable was the change from baselil
`to day 14 in rhinitis symptom severity based onthe combin
`morning and evening 12-hour reflective TNSS. Seu
`efficacy variables were (1) change from baseline .0 day Ie ;
`QoL variables using the RQLQ and (2) change from basellt i
`
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`OLEELEEE
`
`individual symptoms. Safety was evaluated by
`io day 14 in
`atient reports of adverse experiences and Vital Sign assess-
`ments,
`including body temperature, systolic and diastolic
`plood pressure, and pulse and respiration rates, which were
`performed at baseline and at the end of the study.
`statistical Analysis
`The study° ample size was based ontheresults of the study
`py Corren et al (ACT JI),° which was conducted in 307
`atients according to a similar protocol, and ontheresults of
`4 double-blind, placebo-controlled pilot study" in which 60
`patients were treated for | week with azelastine nasal spray,
`fluticasone nasal spray, cetirizine tablets, or placebo. An
`effect size ([azelastine mean — cetirizine mean]/pooled SD) of
`0.25 to 0.35 wasidentified for change in TNSS from baseline
`io day 14. Consideringthis effect size, it was determined that
`150 to 175 patients per treatment group would be sufficient to
`detect differences between groups at the a = .05 level of
`significance with 80%power. The primary analysis was an
`intention-io-treat (ITT) analysis that included all randomized
`patients with at least 1 postbaseline TNSS evaluation. Miss-
`ing TNSSs in the ITT population were imputed using the
`jast-observation-carried-forward method.
`For the primary efficacy variable (change in the TNSS
`from base ine to day 14), the baseline score was calculated as
`the average of the combined morning and evening TNSSs
`during the placebo lead-in period. The change from baseline
`to day 14 was determined by subtracting the mean baseline
`score from the mean TNSS for the entire 14-day treatment
`period.
`\Vithin-group comparisons were made using the
`paired ¢
`test, and between-group comparisons were made
`using an analysis of variance (ANOVA) model. The change
`from baseline in individual symptom severity scores was
`evaluated using a similar ANOVA model. The change in
`INSS from baseline was also calculated for each individual
`day of the study, with baseline defined as the average of the
`combined morning and evening TNSSs during the lead-in
`period. Within- and between-group comparisons were made
`using the paired ¢ test and ANOVA,respectively.
`The QoL evaluation was performed using the self-admin-
`istered RQLQ, which evaluated the following 7 domains and
`components: (1) activities (3 most important as identified by
`the patient), (2) sleep (difficulty getting to sleep, waking up
`during the night, lack of a good night’s sleep), (3) nonnose/
`lloneye symptoms(fatigue, thirst, reduced productivity, tired-
`less, poor concentration, headache, worn out), (4) practical
`Problems (inconvenience of having to carry tissues or a
`tandkerchief, need to rub nose/eyes, need to blow nose
`peatedly),
`(5) nasal
`symptoms
`(stuffy/blocked,
`runny,
`steezinz, postnasal drip), (6) eye symptoms(itchy, watery,
`‘ore, swollen), and (7) emotional factors (frustrated,
`impa-
`lent or restless,
`irritable, embarrassed by symptoms). The
`thange from baseline to day 14 in the RQLQ domain and
`erall scores was calculated and analyzed according to the
`Method described by Juniperet al.'® Baseline demographics,
`tlinical characteristics, and safety data were summarized
`
`descriptively. The safety analysis included all the patients
`whoreceived at least | dose of study medication and had at
`least 1 safety evaluation after drug administration.
`
`RESULTS
`
`Patients
`A total of 360 patients were randomized to double-blind
`treatment; however, postbaseline observations were missing
`for 6 patients. Therefore, data from 354 patients were in-
`cluded in the primary analysis of the ITT population. The
`evaluable patient population consisted of 342 patients who
`completed the 2-week study as per protocol. Nine patients
`discontinued before completing the 2-week treatment period:
`7 in the azelastine group (4 experienced adverse events, 1 was
`lost to follow-up, and 2 for administrative reasons) and 2 in
`the cetirizine group (1 had an adverse event and | waslost to
`follow-up). Three patients completed the 2-week protocol but
`were not considered evaluable due to protocol violations. The
`treatment groups were comparable regarding demographic
`characteristics (Table 1). The patients ranged in age from 12
`to 74 years (mean age, 35 years); 58% were female and 42%
`were male; and 78% were white, 7% were black, 5% were
`Asian, and 10% were of another racial background. The
`average duration of SAR was 18.4 years in the azelastine
`group and [8.7 years in the cetirizine group.
`
`Primary Efficacy
`The combined morning and evening 12-hour reflective TNSS
`wassignificantly improved compared with the baseline score
`in both treatment groups during the 2-week double-blind
`treatment period (P < .001).
`In the ITT population,
`the
`mean + SD baseline TNSS was 18.7 + 3.1 with azelastine
`nasal spray (n = 179) and 19.1 + 3.2 with cetirizine (n =
`175). In the evaluable population, the mean + SD baseline
`TNSS was 18.7 + 3.1 with azelastine nasal spray (n = 174)
`and 19.1 + 3.1 with cetirizine (n = 168). In the primary
`analysis of the ITT population, the mean + SD improvement
`from the baseline TNSS was 4.6 + 4.2 with azelastine nasal
`spray and 3.9 = 4.3 with cetirizine (P = .14). The percentage
`change was 23.9% with azelastine nasal spray and 19.6%
`with cetirizine (P = .08). In the evaluable population, the
`
`Table 1. Demographic Characteristics of the Study Population
`Azelastine nasal
`Cetirizine
`Characteristic
`spray group
`group
`
`(n = 179)
`(n = 175)
`
`72 (40.2)
`107 (59.8)
`
`Sex, No. (%)
`M
`F
`Race, No. (%)
`136 (77.7)
`139 (77.7)
`White
`15 (8.6)
`9 (5.0)
`Black
`7 (4.0)
`9 (5.0)
`Asian
`17 (9.7)
`22 (12.3)
`Other
`
`Age, mean (range), y 34.3 (12-74) 35.1 (12-64)
`
`
`77 (44.0)
`98 (56.0)
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`Figure 1, Mean daily improvements from baseline to day 14 in combined
`morning and evening 12-hour reflective total nasal symptom scores (TNSSs)
`in the intention-to-treat (A) and evaluable (B) patient populations. *P < .05
`vs cetirizine (statistical significance for the entire 14 study days: intention-
`to-treat population, P = .14; evaluable population, P = .09).
`
`mean + SD improvementfrom baseline was 4.6 + 4.2 with
`azelastine nasal spray and 3.8 + 4.3 with cetirizine (P = .09),
`and the percentage improvement was 24.2% with azelastine
`nasal spray and 19.2% with cetirizine (P = .046). Patients in
`both treatment groups experienced increasing improvements
`in the TNSS as the study progressed. Individual daily im-
`provements for the ITT and evaluable patient populations are
`shownin Figure 1.
`
`SecondaryEfficacy
`Change from baseline to day 14 in RQLO scores. Each
`individual RQLQ domain score and the overall RQLQ score
`were significantly improved from baseline in both treatment
`groups (P < .001). Azelastine nasal spray significantly im-
`proved each domain of the RQLQ, including the nasal symp-
`toms domain (P = .05), and the overall RQLQ score (P =
`.002) compared with cetirizine (Fig 2).
`
`Change from baseline to day 14 in individual symptoms. In
`the ITT population, the 4 individual symptoms of the TNSS
`were significantly improved during the 14-day study with
`
`RQLaQ
`Score
`
`Sleep
`
`Nonnose/
`Noneye
`Symptoms
`
`Practical
`Problems
`
`Eye
`Nasal
`Symptoms Symptoms
`
`Emotions.
`
`Figure 2. Mean improvement from baseline to day 14 in overs'l Rhino.
`conjunctivitis Quality of Life Questionnaire (RQLQ) score and individual
`RQLQ domainscores (intention-to-treat population). *P = .05 vs
`cetirizine.
`**P < O1 ys cetirizine.
`
`both treatments compared with baseline scores (P = .03),
`Improvements in the 4 symptoms of the TNSS favored
`azelastine nasal spray overcetirizine, and statistically signif-
`icant improvements in favor of azelastine nasal spray were
`observed for nasal congestion (P = .049) and sneezing (P =
`.O1) (Fig 3).
`
`4
`
`~~
`
`Safety
`Azelastine nasal spray and cetirizine were well tolerated in
`this study. The most common adverse event with azelastine
`nasal spray was bitter taste (7.7%). All other adverse events
`in both treatment groups, including somnolence, headache,
`epistaxis, and pharyngolaryngeal pain, occurred wit) an iM
`cidence of less than 2%. Four patients in the azelastine group
`discontinued the study because of adverse events (headache
`and fatigue, unexpected pregnancy, elevated blood pressure,
`and cough). One patientin the cetirizine group discontinued
`because of vomiting and gastrointestinal distress. There wert
`
`@ Azelastine Nasal Spray
`
`& Cetirizine
`
`FromBaseline,%
`Improvement
`
`Sneezing
`Runny Nose
`Nasal Congestion
`Itchy Nose
`;
`.
`.
`eae dual
`;
`Figure 3. Percentage improvement from baseline to day 14 in individ
`symptom scores (intention-to-treat population). *P =. 049 vs cetiri#!
`**P = Q1 vs cetirizine.
`
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`to posttreatment
`significant pretreatment
`inically
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`in vital signs in either treatment group.
`changes !
`re
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`pIscUSSION
`Previous comparative studies!"'® of oral antihistamines in
`SAR gene rally have not shown significant differences be-
`tween agents when evaluated across |4-day study periods.
`For ACT i,)? it was hypothesized that an intranasally admin-
`istered antihistamine should have a greater effect on symp-
`joms than an oral second-generation antihistamine, due in
`part to greater local concentrations of active drug in the nasal
`mucosa.
`In that study,
`it was shown that azelastine nasal
`spray was significantly more effective than oral cetirizine for
`ireating nasal symptomsand for improving the overall RQLQ
`score in patients with moderate-to-severe SAR.
`In the present study, azelastine nasal spray and cetirizine
`significantly improved the TNSSandindividual symptomsof
`the TNSS compared with baseline scores overall and on each
`day of the study. Rapid relief of rhinitis symptoms was
`evident
`in both groups at
`the first evaluation after initial
`administration. Azelastine nasal spray continuously improved
`the TNSS during the 14 study days, with the greatest degree
`of improvement during the second week of treatment. Dif-
`ferences in the TNSS between azelastine nasal spray and
`cetirizine were notstatistically significant; however, the mag-
`nitude of improvement favored azelastine nasal spray over
`cetirizine on each of the 14 study days. In addition, there was
`astatisticaily significant difference favoring azelastine nasal
`spray for overall percentage improvementin the TNSS in the
`evaluable patient population. Although there were no differ-
`ences between treatment groups in TNSS, a statistically sig-
`nificant difference favoring azelastine nasal spray over ceti-
`rizine was seen in the nasal symptoms domain of the RQLQ,
`which reflects improvement in the severity of nasal symp-
`toms on the last day of the 14-day study.
`Regarding individual symptoms, azelastine nasal spray sig-
`nificantly improved sneezing and nasal congestion compared
`with cetirizine. The positive effect of azelastine nasal spray
`on congestion was observeddespite the fact that the cetirizine
`group had the added benefit of daily use of a placebo saline
`spray. Based on data from ACT I and ACT II, nasal conges-
`tion seems to be the most difficult symptom to treat in the
`thinitis symptom complex.
`In ACT I, the improvement in
`hasal congestion with azelastine nasal spray was 21.1% com-
`pared with a placebo response of 18.1%, whereas in ACT II,
`the improvement in nasal congestion with azelastine nasal
`‘pray was 18.0% compared with a placebo response of
`12.6%,
`It seems that the failure to demonstrate a statistical
`difference between treatments in ACT I was dueto the high
`Placebo response rate in that study.
`The ability of azelastine nasal spray to improve nasal
`“ongestion has previously been reported in multicenter pla-
`“tbo-controlled trials in SAR! and nonallergic vasomotor
`thinitis.2° The importance of effectively treating nasal con-
`s*stion was demonstrated in a large open-labeltrial?! involv-
`Ng more than 4,000 patients with SAR, nonallergic vasomo-
`
`(seasonal allergies with
`rhinitis, or mixed rhinitis
`tor
`sensitivity to nonallergic triggers) in which nasal congestion
`was reported as the most bothersome rhinitis symptom by
`52%of the patients. In this trial, azelastine nasal spray was
`reported to control all rhinitis symptoms,
`including nasal
`congestion, regardless of rhinitis diagnosis, and patients with
`mixed rhinitis were identified as a subgroup most likely to
`respond to treatment with azelastine nasal spray.
`The RQLQis a standardized disease-specific questionnaire
`that was developed to measure physical, emotional, and so-
`cial problemsthat are troublesometo patients with rhinocon-
`junctivitis.?” The RQLQ has been methodologically validated,
`is reproducible in patients with stable rhinitis, and has been
`determined to be capable of detecting clinically meaningful
`changes in QoL variables.'® As in ACT I,in the presentstudy,
`all
`the individual domains of the RQLQ and the overall
`RQLQ score were significantly improved from baseline in
`both treatment groups. Although oral cetirizine significantly
`improved RQLQscores, patients treated with azelastine nasal
`spray reported additional statistically significant
`improve-
`ment beyondthat reported with cetirizine for each individual
`RQLQ domain, including the nasal symptoms domain, and
`for the overall RQLQscore. Althoughit is often assumedthat
`patients prefer oral medications to sprays, in ACT I and ACT
`II, patients reported superior improvements in QoL variables
`with azelastine nasal spray compared with oral cetirizine. The
`clinical benefits of topical therapy with azelastine are evident
`in the consistent outcomes of ACT I and ACT II. In both
`trials, there were no times during the 14-day TNSS evaluation
`periods, no individual symptom assessments, and no individ-
`ual domains of the RQLQ where azelastine nasal spray was
`not numerically or statistically better than cetirizine.
`Rhinitis is a significant cause of widespread morbidity, and
`although often incorrectly viewed as a nuisance disease, the
`symptoms ofrhinitis can have a major impact on the patient’s
`QoL by interfering with sleep, causing fatigue, and impairing
`daily activities and cognitive function.! Although individual
`symptoms of AR may be particularly bothersome,it is often
`the impact of these symptoms on daily activity and well-
`being that causes the patient to seek medical care.** As an
`example of the magnitudeof this effect, in a study of patients
`with perennial AR, Bousquetet al”* reported that QoL tended
`to be worse in 7 of 9 health-related domains among patients
`with rhinitis compared with those with asthma.
`The Joint Task Force on Allergy Practice and Parameters
`advises that improving the negative impact on daily life in
`patients with rhinitis defines successful treatment as much as
`providing symptom relief.' The value of health-related QoL
`assessments in rhinitis is the emphasis that is placed on the
`patient’s perspective in assessing the functional effects of the
`illness and the therapy.* As recommended by Juniper,”° for
`most patients with rhinitis, and in particular for patients with
`SAR, improving patient well-being and QoL should be the
`primary goal of treatment.
`The use of topical therapy is appropriate in the treatment of
`SAR. Delivering medication directly to the site of allergic
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`inflammation has an inherent advantage over oral therapy.
`The higher concentrations of antihistamines that can be
`achieved in the nasal mucosa by topical as opposed to oral
`administration should enhance the antiallergic and potential
`anti-inflammatory effects of these agents, making targeted
`delivery to the site of inflammation an important consider-
`ation in selecting therapy for rhinitis.
`In addition,
`topical
`administration should minimize the risk of interactions with
`concomitant medications.*’ The benefits of topical antihista-
`mine therapy have been demonstrated in placebo-controlled
`clinical studies with oral antihistamines in which azelastine
`nasal spray was effective in treating patients who remained
`symptomatic after treatment with oral loratadine** or fexofe-
`nadine.’ In these studies, no additional clinical benefit was
`seen with azelastine nasal spray combined with oral agents
`compared with treatment with the nasal spray alone.
`This study was double-blinded such that each patient re-
`ceived either an identity-concealed bottle of azelastine nasal
`spray plus placebo capsules or encapsulated cetirizine tablets
`plus placebo/saline nasal spray. The beneficial effect of in-
`tranasal saline on chemical mediators of inflammation and
`symptoms of rhinitis has been documented in clinical tri-
`als.*°?! In effect, patients in the cetirizine group were taking
`an active second therapeutic agent (saline nasal spray) in
`addition to the oral antihistamine. The use of a saline spray
`placebo in the cetirizine group might reduce the difference
`between the 2 groups, thereby making it more difficult to
`achieve a statistically significant separation between treat-
`ments. As such, the difference in the TNSS between azelas-
`tine nasal spray and cetirizine oral
`tablets may in fact be
`greater than the difference observed in this study.
`Azelastine nasal spray and cetirizine were well tolerated in
`this study. Althoughrelatively high incidences of somnolence
`and bitter taste were reported in early trials!?#**> with azelas-
`tine nasal spray, subsequent trials in patients with vasomotor
`rhinitis”? and postmarketing studies in patients who remained
`symptomatic after treatment with loratadine** or fexofena-
`dine*? reported somnolence rates with azelastine nasal spray
`that were similar to those with placebo. The lower incidence
`of azelastine-related adverse events in the latertrials is most
`likely due to using a proper dosing technique, in which the
`drug is administered without tipping the head backward or
`deeply inhaling the spray, thereby minimizing the potential
`for systemic absorption, which could result in bitter taste and
`somnolence.
`
`CONCLUSIONS
`This study was conducted to compare the use of azelastine
`nasal spray vs cetirizine oral
`tablets for improving nasal
`symptomsand health-related QoL variables in patients with
`SAR. Azelastine nasal spray and cetirizine were effective in
`treating nasal symptomsin patients with moderate-to-severe
`SAR. In the primary analysis, although not achieving statis-
`tical significance, improvement in the TNSS and individual
`symptom scores favored azelastine nasal spray over cetiriz-
`ine, and statistically significant differences favoring aze