1‘NNALS OF
`
`Allergy, Asthma
`& Immunology
`
`”)t't‘ici al Publication of the American College of
`
`Cover Photo/Lombardy Poplar
`
`Al]e1gy.Asthma 8: Immunology Contents of Annals of Allergy, Asthma &
`
`Popular nigra
`
`Immunology Copyright © 2006 by the American
`College of Allergy, Asthma & Immunology.
`EDITOR: Gailen D. Marshall. Ml, PhD
`Annals of Allergy, Asthma & Immunology
`University of Mississippi Medical Center
`2500 North State Street
`Jackson; "MS 39216
`(60]) 815-5527
`.
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`gmarshall@medicinerurnsmededu
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`Sensitization to poplar pollen has been foana’ in _
`allergic asthmatics, .
`. .”
`.
`(I efer to page A6)
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`‘
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`_
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`‘
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`VOLUME 97, SEPTEMBER, 2006
`
`IN MEMORIAM
`
`John C. Selner, MD, February 5, 1936, to July 20, 2006 ........................................................ 269
`Gailen Marshall, MD, PhD
`
`
`GUEST EDITORIAL
`
`Specific polysaccharide antibody deficiency ............................................................................. 271
`Charles H. Kirkpatrick, MD
`
`
`CME REVIEW ARTICLE
`
`Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal
`neerolysis ..................................................................................................................................... 272
`Barzin Khalili, MD, and Sami L. Balma, MD, DrPH
`
`CASE REPORTS
`
`Lack of cross-reactivity between S-aminosalicylic acid—based drugs: a case report and review
`of the literature ............................................................................................................................ 284
`
`Shiang-Ja Kong, MD; Cuckoo Cliondliary, MD; Stephen J. Mc‘Geady, MD and
`John R. Colin, Ml)
`
`Improvement of asthma control with omalizumab1112obese pedldtl1c asthma patients ........ 288
`Kenn} I". C Kwong, MD, and Craig A. Jones, MD
`
`Clustered sensitivity to l'ungi: anaphylactic reactions caused by ingestive allergy
`to yeasts ....................................................................................................................................... 294
`Krisriina Airolo, MD, PhD; Leena Peonan and Salli Malcinen-Kilfnnen, PhD
`
`
`REVIEW
`
`Use of the Health Plan Employer Data and Information Set for measuring and
`improving the quality of asthma care ........................................................................................ 298
`Erwin W. Gelfancl, MD; Gene L. Colir'e, MD; Leonard Fminer, MD, FAAFP;
`William B. Bonn [11, MD. JD, MPH and Thomas J. Davies, JD. MFA
`
`‘
`
`Exhibit 1162” '
`Exhibit 1162
`{Continued on page A7)
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`'
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`IPR2017-00807
`QQQQQ]
`IPR2017—00807
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`ARGENTUM
`A5
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`rm; material may be protected by Copyright law (Title 17 u 5 Code)
`
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`
`
`ff—E
`Impact 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, MDT; Jonathan Bernstein, MD:; Shailen Shah, MD§;
`Harry Sacks; MD‘fl; and Eli O. Meltzer, MDH
`
`
`Background: In fall 2004, the first Azelastine Cetirizine Trial demonstrated statistically significant improvements in the total
`nasal symptom score (TNSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores with the use of azelastine
`nasal spray vs oral cetirizine in patients with seasonal allergic rhinitis (SAR).
`objective: To compare the effects of azelastine nasal spray vs cetirizine on the TNSS and RQLQ scores in patients with SAR.
`Methods. This 2-week, double-blind, multicenter trial randomized 360 patients with moderate-to—severe SAR to azelastine,
`25pray5 per nostril twice daily, or cetirizine, lO-mg tablets once daily. The primary efficacy variable was the 12-hour reflective
`TNSS (rhinorrhea, sneezing, itchy nose, and nasal congestion). Secondary efficacy variables were individual symptom scores and
`the RQLQ core.
`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 E .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. Improvements in
`the TNSS and individual symptoms favored 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.
`Ann Allergy Asthma Immortal. 2006;97:375—381.
`
`INTRODUCTION
`
`‘
`
`Allergic rhinitis (AR) is one of the most common diseases 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.'2 The various
`forms of nonallergic rhinitis have been reported to affect 15
`to 20 million persons in the United States.3 In addition to AR
`‘ and nonall'trgic rhinitis, estimates suggest that 22 million to
`26 million persons have mixed rhinitis,
`ie, seasonal AR
`‘ (3A5), Wi-h exacerbations from exposure to nonallergic trig-
`gers. '5
`
`. Azelastine nasal spray is a topically administered second—
`generatior. antihistamine indicated for the treatment of SAR
`. and nonallergic vasomotor rhinitis. Azelastine is a phthalazi-
`“9116 deri.ative and represents a unique class of antihista—
`‘mlnes. The primary mechanism of action of azelastine is
`1‘1
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`:SDUIhern California Research, Mission Viejo. California.
`LCentrai Tr-tas Health Research, New Braunfels, Texas.
`i éBfirnstein Clinical Research Center, Cincinnati. Ohio.
`iAllergy an 1 Asthma Consultants of NJ—PA PC, Collegeville, Pennsylvania.
`ElMedPoinIc Pharmaceuticals, Somerset, New Jersey.
`’ Ellilfergy 81 Asthma Medical Group & Research Center APC, San Diego,
`Dona.
`, Eundlflg for this study was provided by MedPointc Pharmaceuticals.
`Enema for publication September 28. 2005.
`A“email in" publication in revised form February 13. 2006.
`
`l
`
`Ill—receptor antagonism. Azelastine also has demonstrated
`inhibitory effects on other mediators of inflammation, includ-
`ing leukotrienes,6 bradykinin and substance P,” cytokines,“
`intercellular adhesion molecule 1 expression,9 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 leukotrienesfl” prostaglandins,l1 intercellular adhe-
`sion molecule 1 expression]2 and eosinophil chemotaxis.l2
`In fall 2004, the effectiveness and tolerability of azelastine,
`2 sprays per nostril twice daily, were compared with those of
`cetirizine, Ill-mg tablets once daily, in a multicenter study of
`307 patients with moderate-to—severe SAR (the first Azelas-
`tine Cetirizine Trial [ACT 1)).13 During the 2-week double-
`blind treatment period, azelastine nasal spray significantly
`improved the overall total nasal symptom score (TNSS) come
`pared with cetirizine (P = .02). Azelastine nasal spray also
`improved all 4 symptoms of the TNSS compared with base—
`line, with significantly greater improvement vs 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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`life (QoL) based on the Rhinoconjunctivitis Quality of Life
`Questionnaire (RQL-Q) 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).
`Outcomes in 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.2 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
`syranOms.l4 The objective of this study was to confirm the
`results of the ACT 1 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 signifir
`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 leadein period; use of oral antihista-
`mines was discontinued for a minimum of 5 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 11) 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 Res
`view Board (Atlanta, GA), and all 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 (Astclin; MedPointe Phar Decem-
`cals. Somerset, NJ) was supplied in polyethylene b0ttleS
`containing 30 mL of study medication. The lO—mg cetirizine:
`tablets (Zyrtec; Pfizer Inc, New York, NY) were encioged in
`a placebo-matching capsule overfilled with lactose. Placeb“
`nasal spray was provided in polyethylene bottles c- ntaimna
`30 mL of vehicle solution. Placebo capsules were filled wit; ,
`lactose. Each patient received either (1) active ale-tasting];
`sprays per nostril twice daily,
`in the morning and evening,
`and a placebo capsule once daily in the morning or 12) actiri ‘
`cetirizine once daily in the morning and placebo na a1 spray.
`_
`2 sprays per nostril twice daily, in the morning and evening. '
`to ensure adequate blinding of the study. The dissolution rates
`of lO—mg cetirizine tablets and 10-mg encapsulated {retirizine "
`tablets overfilled with lactose were shown to be almost iden.
`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.é
`ceuticals, data on file).
`Patients who met the inclusion and exclusion criteria wens
`randomized to treatment groups by means of a zomputer—
`generated randomization schedule. The randomization sched- .
`ule was provided by the biostatistical group (i3 .itatprube,
`Ann Arbor, MI) employed by the sponsor, and access to the ,
`random code was confidential and accessible only to autho-
`rized persons who were not involved in the study. P linding of
`the study was preserved at each study site 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 nasal
`spray and placebo capsules and recorded their 12-1“ . .ur reflec- '
`tive rhinitis symptom severity scores twice daily (morning
`and evening) in diary cards to determine their eligibility f0”
`entry into the double-blind treatment period. Symptom sever-
`ity was determined by the TN SS, which consisted of runnl‘t
`nose, sneezing, nasal
`itching, and nasal congest'an scored
`twice daily (morning and evening) on a severity scale from0 t
`to 3 (0 = none,
`1 = mild, 2 = moderate, and 3 : sevetfll.
`such that the maximum possible daily TNSS was '74. Patients t
`qualified for entry into the lead~in period if they had a TNSS
`of at least 8 and a nasal congestion score of at he:
`t 2 during a,
`the previous 12 hours and met all the study inclusion and
`exclusion criteria. To be eligible for entry into his doulfilfi‘e
`blind treatment period, patients must have recorded eithfifa
`morning or evening TNSS of at least 8 on at least 3 (131's
`during the lead-in period and a morning or even 1g 13011365—i
`tion score of 3 on at
`least 3 days. For TNSS and “3911*
`congestion,
`1 of the 3 days selected must ham: Occumd'
`within 2 days of study day l.
`i-
`
`,
`Efiicacy and Safety Variables
`The primary efficacy variable was the change from basellfl" ‘
`to day 14 in rhinitis symptom severity based on t‘" 7 Comma;
`morning and evening 12-hour reflective TNSS. secondai'l“
`efficacy variables were (1) change from baseline 0 day 14.13
`QoL variables using the RQLQ and (2) change fmm basellfl
`
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`individual symptoms. Safety was evaluated by
`to day 14 7:
`iienl reports of adverse experiences and Vital sign assess-
`pa nts mus-ding body temperature, systolic and diastolic
`fizod'pressure, and pulse and respiration rates, which were
`performed at baseline and at the end of the study.
`Statistical i dialysis
`The study ' ample size was based on the results of the study
`by CortB-n et al (ACT D,” which was conducted in 307
`patients at urding to a similar protocol. and onithe results of
`a double-blind, placeboscontrolled pilot study” in which 60
`patients Were treated for 1 week With azelastine nasal spray,
`flutieasonc nasal spray, cetirizine tablets, or placebo. An
`effect size (I azelastine mean — cetirizine meanj/pooled SD) of
`0.25 to 0.? ' was identified for change in TN SS from baseline
`[0 day 14, Considering this 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-ig—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
`last—obser‘ :ttion—carried—forward method.
`For the primary efficacy variable (change in the TNSS
`from basr Lne 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 1a was determined by subtracting the mean baseline
`score from the mean TNSS for the entire 14—day treatment
`period.
`‘- «s'ithin-group comparisons were made using the
`paired t
`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
`TNSS 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 betweenwgroup comparisons were made
`using the paired r test and ANOVA, respectively.
`The (AL 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/
`Honeyc symptoms (fatigue, thirst, reduced productivity, tired-
`Hess, poor concentration, headache, worn out), (4) practical
`Problems (inconvenience of having to carry tissues or a
`handkerchief, need to rub nose/eyes, need to blow nose
`repeatedly),
`(5) nasal
`symptoms
`(stuffy/blocked,
`runny,
`SHeezing. postnasal drip), (6) eye symptoms (itchy, watery,
`We. swollen), and (7) emotional factors (frustrated,
`impa-
`llEHt or restless,
`irritable, embarrassed by symptoms). The
`Ch‘rlIlge from baseline to day 14 in the RQLQ domain and
`0Verall scores was calculated and analyzed according to the
`mythoc described by Juniper et a1.16 Baseline demographics,
`CllIticaI characteristics, and safety data were summarized
`
`descriptively. The safety analysis included all the patients
`who received at least 1 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 ( l had an adverse event and 1 was lost to
`follow—up). Three patients completed the 2Awee1< protocol but
`were not considered evaluable due to protocol violations. The
`treatment groups were comparable regarding demographic
`characteristics (Table l). 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 18.7 years in the cetirizine group.
`
`Primary Ejj‘icacy
`The combined morning and evening 12-h0ur reflective TNSS
`was significantly 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 i SD baseline TNSS was 18.7 i 3.1 with azelastine
`
`nasal spray (n = 179) and 19.1 i 3.2 with cetirizine (n =
`175). In the evaluable population, the mean : SD baseline
`TNSS was 18.7 i 3.1 with azelastine nasal spray (n = 174)
`and 19.1 i 3.1 with cetirizine (n = 168). In the primary
`analysis of the ITT population, the mean i SD improvement
`from the baseline TNSS was 4.6 i 4.2 with azelastine nasal
`
`spray and 3.9 i 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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`MeanImprovementFromBaseline
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`Activates
`
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`
`Overall
`RQLQ
`Score
`
`Nonnosei
`Noneye
`Symptoms
`
`Practical
`Problems
`
`Eye
`Nasal
`Symptoms Symptoms.
`
`
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`
`
`
`
`MeanImprovementFrom
`
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`
`MeanImprovementFrom
`
`BaselineinTNSS
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`l
`
`2
`
`3
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`4
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`5
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`6
`
`7
`
`8
`
`9
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`10
`
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`
`13
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`
`StudvDay
`
`BaselineinTNSS
`
`1234567891011121314
`SIudyDay
`
`+Azetastine Nasal Spray +Cetirizine
`
`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 intentionatoatreat (A) and evaluable (B) patient populations. *P < .05
`vs cetirizinc (statistical significance for the entire 14 study days: intention
`to—Lreat population. P : .14; evaluable population, 1’ = .09).
`
`mean i SD improvement. from baseline was 4.6 i 4.2 with
`azelastine nasal spray and 3.8 i— 4.3 with cetirizine (P = .09),
`and the percentage improvement was 24.2% with azelastine
`nasal spray and 19.2% with cetirizine (P r .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
`shown in Figure 1.
`
`Secondary Efficacy
`Change from baseline to day 14 in RQLQ scores. Each
`individual RQLQ domain score and the overall RQLQ score
`were significantly improved from baseline in both treatment
`groups (P < .001). Azelastinc nasal spray significantly im-
`proved each domain of the RQLQ, including the nasal symp-
`toms domain (P S .05). and the overall RQLQ score (P =
`.002) compared with cetirizine (Fig 2).
`
`Changejrom. 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
`
`,-
`
`1:
`
`Figure 2. Mean improvement from baseline to day 14 in over: ‘I Rhino.
`conjunctivitis Quality of Life Questionnaire (RQLQ) score and individual
`RQLQ domain scores (intentionimitreat population). *P E .05 vs
`etirizine.
`‘H‘P < .01 vs cetirizine.
`
`both treatments compared with baseline scores (P E .03).
`Improvements in the 4 symptoms of the TNSS favored
`azelastine nasal spray over cetirizine, and statistically signii
`icant improvements in favor of azelastinc nasal spray were
`observed for nasal congestion (P = .049) and sneezing (P =
`.0!) (Fig 3).
`
`Safety
`Azeiastine nasal spray and cetirizine were well tolerated in
`this study. The most common adverse event with acelastine
`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 in-
`cidence of less than 2%. Four patients in the azelastine group
`discontinued the study because of adverse events (Eeadache
`and fatigue. unexpected pregnancy. elevated blood pressure.
`and cough). One patient in the cetirizine group discontinued
`because of vomiting and gastrointestinal distress. Tia “re were
`
`
`
`improvementFromBaseline.sin
`
`I Azeiastine Nasal Spray
`
`as Cetin‘zine
`
`
`
`Itchy Nose
`
`Nasal Congestion
`
`5' 992mg
`Runny Nose
`.
`-
`-.r ual
`.
`.
`.
`.
`Figure 3. Percentage improvement Irom baseline to day 14 m indnitl
`.
`symptom scores (intention—to—treal population).
`="-P =. 049 \\
`*l‘P : .01 vs cetirizine.
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`to posttreatment
`significant pretreatment
`[10 CllHlL. Sly
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`Changes in vital signs in either treatment group.
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`DISCUSS‘ON
`PreleUS comparative- studies”18 of oral antihistamines in
`5AR gen. rally have not shown significant differences be-
`tween agents-when evaluated across l4-lday study periods.
`For ACT i.” it was hypotheSized that an intranasally admin
`istered antihistamine should have a greater effect on symp-
`toms than an oral second-generation antihistamine, due in
`part to git
`ter local concentrations of active drtig in the nasal
`mucosa.
`In that study,
`it was shown that azelastiiie nasal
`spray was significantly more effective than orai cetirizine for
`treating n1! -.: a] symptoms and for improving the overall RQLQ
`score in patients with moderate-to—severe SAR.
`In the 1: 'esent study, azelastine nasal spray and cetirizine
`significantly improved the TNSS and individual symptoms of
`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
`administrzi-‘ion. Azelastine nasal spray continuously improved
`the TNSS during the 14 study days, with the greatest degree
`of improvement during the second week of treatment. Diff
`ferences in.
`the TNSS between azelastine nasal spray and
`cetirizine were not statistically significant; however, the mag-
`nitude of improvement favored azelastine nasal spray over
`cetirizine on each of the 14 study days. In addition, there was
`a statisticady significant difference favoring azelastine nasal
`spray for overall percentage improvement in the TNSS in the
`evaluable patient population. Although there were no differ—
`ences bet‘. "sen 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 liiC last day of the 14-day study.
`Regarding individual symptoms, azelastine nasal spray sig
`nificantly improved sneezing and nasal congestion compared
`with cetii'..:.iiie. The positive effect of azelastine nasal spray
`on congestion was observed despite the fact that the cetirizine
`gYOUp had the added benefit of daily use of a placebo saline
`Spray. Bar ed on data from ACT I and ACT II, nasal conges-
`tion seems to be the most difficult symptom to treat in the
`rhinitis sginptom complex.
`In ACT I, the improvement in
`nasal congestion with azelastine nasal spray was 21.1% com-
`Pared With a placebo response of 18.1%, whereas in ACT II,
`the impro'ement in nasal congestion with azelastine nasal
`Spray Was 18.0% compared with a placebo response of
`133%.
`It seems that the failure to demonstrate a statistical
`difference between treatments in ACT I was due to the high
`placebo IIAPOI'ISC rate in that study.
`The ability of azelastine nasal spray to improve nasal
`CongeSllUll has previously been reported in multicenter pla-
`CE5_l3ff-t:onf..i;illed trials in SAR‘E’ and nonallergic vasomotor
`rhinitis?” The importance of effectively treating nasal cone
`station was demonstrated in a large open-label trial“ involv—
`trig 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 RQLQ is a standardized disease-specific questionnaire
`that was developed to measure physical, emotional, and so—
`cial problems that are troublesome to patients with rhinocon-
`junctivitis.22 The RQLQ has been methodologicaily validated,
`is reproducible in patients with stable rhinitis, and has been
`determined to be capable of detecting clinically meaningful
`changes in QoL variables.16 As in ACT I, in the present study,
`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 RQLQ scores, patients treated with azelastine nasal
`spray reported additional statistically significant
`improve~
`ment beyond that reported with cetirizine for each individual
`RQLQ domain, including the nasal symptoms domain, and
`for the overall RQLQ score. Although it is often assumed that
`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 of rhinitis can have a major impact on the patient’s
`QoL by interfering with sleep, causing fatigue, and impairing
`daily activities and cognitive function.l Although individual
`symptoms of AR may be particalarly bothersome, it is often
`the impact of these symptoms on daily activity and well—
`being that causes the patient to seek medical care.23 As an
`example of the magnitude of this effect, in a study of patients
`with perennial AR, Bousquet et al24 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.25 As recommended by Juniper,26 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.27 The benefits of topical antihistaa
`mine therapy have been demonstrated in placeboacontrolled
`clinical studies with oral antihistamines in which azelastine
`
`nasal spray was effective in treating patients who remained
`symptomatic after treatment with oral loratadinezg 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 identityiconcealed 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.3°-3‘ 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. Although relatively high incidences of somnolence
`and bitter taste were reported in early trials'9-32‘35 with azelas-
`tine nasal spray, subsequent trials in patients with vasomotor
`rhinitis20 and postmarketing studies in patients who remained
`symptomatic after treatment with loratadine28 or fexofena-
`dine29 reported somnolence rates with azelastine nasal spray
`that were similar to those with placebo. The lower incidence
`of azelastine-related adverse events in the later trials 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
`symptoms and health-related QoL variables in patients with
`SAR. Azelastine nasal spray and cetirizine were effective in
`treating nasal symptoms in pa