A double-blind, controlled trial to assess the
`
`safety and efficacy of azelastine nasal spray in
`seasonal allergic rhinitis
`
`Paul H. Ratner, MD,“ Steven R. Findlay, MD,” Frank Hampel, Jr., MD,°
`Julius van Bavel, MD,‘ Michael D. Widlitz, MD,’ and
`
`Jeffrey J. Freitag, MD’
`
`San Antonio, Austin, and New Braunfels, Texas, and Princeton, N.J.
`
`Background: Azelastine solution is a topically (nasal) administered antiallergy drug with a
`preclinical profile suggestive of efficacy in patients with allergic rhinitis.
`Objectives: The study was designed to compare the efiectiveness and safety of two dosages of
`azelastine nasal spray (2 sprays per nostril once daily and twice daily) with that ofplacebo
`in the treatment ofpatients with symptomatic seasonal allergic rhinitis.
`Methods: Two hundred fifty-one patients (12 years of age or older) were randomized to
`treatment in this 2-week, double-blind, parallel-group study. Primary efiicacy variables were
`Major Symptom Complex (nose blows, sneezes, runny nose, itchy nose, watery eyes) and Total
`Symptoms Complex (Major Symptom Complex plus itchy eyes/ears/throat/palate, cough,
`postnasal drip).
`Results: Patients treated with azelastine had mean percent improvements in Total and Major
`Symptom Complex scores that were consistently superior to placebo at each evaluation point.
`Overall, improvements were statistically significant (p S 0.05) in the Total Symptoms Complex
`for both azelastine groups and in the Major Symptom Complex for the twice daily group with
`a trend toward statistical significance for the once daily group. Azelastine was superior to
`placebo in improving all individual rhinitis symptoms. Adverse experiences in the azelastine
`groups were minor and infrequent.
`Conclusion: The results support the efiicacy and safety of azelastine nasal spray in the
`treatment of seasonal allergic rhinitis. (J ALLERGY Curv Iurwurvor. I 994,'94.'8I8-25.)
`
`Key words: Azelastine nasal spray, symptomatic seasonal allergic rhinitis, Major Symptom
`Complex, Total Symptom Complex
`
`Azelastine hydrochloride is an investigational
`antiallergic compound that has been shown in
`human and animal model systems to inhibit the
`synthesis or target receptor activity of a broad
`spectrum of biologic mediators of allergy and
`airway hyperreactivity including histamine," 2 leu-
`
`kotrienes,’ " TAME—esterase,5 acetylcholine," se-
`
`Abbreviations used:
`b.i.d.: Twice a day
`MSC3 M3l0f SYmP10m C0mP1€X
`Nasal Spray
`Once a day
`Seasonal allergic rhinitis
`Total Symptom Complex
`
`From “Sylvana Research, San Antonio; "Findlay Research
`rotoninp, as and bradykininp The effects of inhib_
`Associates. lnc., Austin; ‘Private practice, New Braunfels;
`.
`.
`.
`.
`.
`.
`-
`.
`dAllergy Associates of the Austin Diagnostic Clinic; and
`iting these mediators include the inhibition of
`cwauace Laboratories, Princeton
`allergic reactions’ interference with inflammatory
`Supported by a grant from Wallace Laboratories, a Division of
`processes, and modulation of airway smooth
`Carter-Wallace, lnc., Cranbury, N.J .
`Received for publication July 7, 1993; revised Apr. 19, 1994; muscle 1~esp0nse_ For these reasons, azelastine
`3°°°Pted f0’ P“b“°a“°“ May 12’ 1994'
`should be characterized as a multifunctional an-
`Reprint requests: Paul H. Ratner, MD, Sylvana Research,
`.
`.
`.
`-
`-
`-
`-
`-
`_
`7711 Louis Pasteur, Suite 406, San Antonio, TX 78229.
`t‘a”°rg'° medmanon because It pmvldes Slgmfi
`Copyright © 1994 by Mosby—Year Book Inc,
`cant therapeutic activity in allergic hayfever and
`009]-6749/94 s3.oo + 0
`1/1/57539
`allergic asthma.”
`818
`
`Exhibi
`
`Exhibit 1050
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 94, NUMBER 5
`
`Rainer et al.
`
`819
`
`Previous short—term studies of azelastine nasal
`
`spray (Astelin NS) have shown that dosage regi-
`mens of 2 sprays per nostril once a day (q.d.) and
`2 sprays per nostril twice a day (b.i.d.) are safe
`and effective in the treatment of seasonal allergic
`rhinitis (SAR)."* ‘2 These studies also demon-
`strated that azelastine nasal spray (NS) has a
`rapid onset of action (within 1
`to 2 hours of
`administration) and a long duration of effect,
`lasting up to 24 hours.
`To alleviate the limiting factors that are often
`associated with SAR trials (e.g., variability and
`duration of the pollen counts),
`this study was
`conducted in south central Texas where pollen
`from the tree Juniperus sabinoides,
`commonly
`called mountain cedar,
`is an important cause of
`respiratory allergy. The mountain cedar pollinates
`heavily during the months of December, January,
`and February and somewhat less so in November
`and March, depending on yearly weather condi-
`tions. In the winter months, the pollen from the
`mountain cedar blows in with “northern fronts”
`
`in significant
`the only pollen present
`and is
`amounts in the air during this time. Mountain
`cedar pollen counts are higher than those ob-
`served with any other seasonal pollen. As such, it
`provides an excellent research model with which
`to evaluate the efficacy of medications in treat-
`ment of po1len—induced respiratory allergy.
`In this study, conducted at four sites in south
`central Texas during the mountain cedar pollen
`season in January and February, the efficacy and
`safety of two dosages of azelastine NS were com-
`pared with efficacy and safety of placebo in the
`long-term treatment of patients with symptomatic
`SAR.
`
`METHODS
`Patients
`
`All patients were at least 12 years old with a history
`and diagnosis of allergic rhinitis requiring therapy for at
`least the previous 2 years and a positive response to
`mountain cedar pollen, as confirmed by a recognized
`prick or scratch test within the past year. A signed
`informed consent document was required before the
`screening period. The consent document
`for those
`under the legal age of consent
`(18 years) was also
`signed by a parent or guardian.
`Patients with a history of asthma could be enrolled if
`they had not taken long-term antiasthma medication
`for at
`least 24 consecutive months before study en-
`trance or if
`they had a history of exercise-induced
`asthma and had used a B-agonist inhaler only in con-
`junction with exercise. Patients with acute exacerba-
`tions of asthma were excluded from study participation.
`
`Pregnant and nursing women were ineligible for
`participation, and women of childbearing potential
`were included only if they used appropriate methods of
`contraception. Patients with an upper respiratory tract
`infection, with clinically significant nasal anatomic de-
`formities, or with other significant medical conditions
`were excluded, as were those who experienced an
`episode of acute sinusitis within 60 days of participation
`and those receiving a changing immunotherapy regimen
`or beginning immunotherapy.
`The following medications were restricted before the
`baseline evaluation: calcium channel blockers, cro-
`molyn, B-blockers, reserpine, or monoamine oxidase
`inhibitors within 14 days; H,—receptor antagonists or
`decongestants within 48 hours; and astemizole within
`60 days. Also ineligible for study participation were
`those patients who had experienced a clinically signif-
`icant adverse drug reaction during a previous drug
`study with azelastine or a similar drug.
`
`Study design
`
`This was a multicenter, double-blind, randomized,
`placebo- and positive-controlled, parallel-group study
`in patients with symptomatic SAR. After a 1-week
`single-blind placebo evaluation period, eligible patients
`who satisfied the minimum symptom criteria (a Major
`Symptom Complex [MSC] score of at least 10 on any 4
`days of the baseline period with at least one symptom
`of moderate or greater intensity on each of the 4 days)
`were randomized to one of four treatment groups:
`azelastine NS, 2 sprays per nostril q.d.
`(total daily
`dose = 0.55 mg), azelastine NS, 2 sprays per nostril
`b.i.d.
`(total daily dose =1.1 mg); chlorpheniramine
`maleate (Chlor-Trimeton Repetabs) 12 mg b.i.d.; or
`placebo, b.i.d. for 2 weeks of treatment.
`Study medication was blinded with a double-dummy
`technique for both the NS and tablets. Patients re-
`ceived medication twice a day; at both times, they took
`the tablet and the NS. For the chlorpheniramine group,
`the NS was matching placebo, and for the azelastine
`groups, the tablet was matching placebo.
`Rhinitis symptoms were recorded at the time of drug
`administration (once in the morning and once in the
`evening) on a diary card. For the symptoms of runny
`nose and sniffles;
`itchy nose; watery eyes;
`itchy eyes,
`ears,
`throat, and palate; cough; postnasal drip; and
`symptom stuffiness the patients used the following scale
`to rate severity: 0 = none; 1 = mild, symptoms barely
`noticeable;
`2 = modest,
`symptoms
`noticeable;
`3 = moderate, somewhat bothersome; 4 = moderately
`severe, interfered with activities; and 5 = severe, con-
`stant distraction. For nose blows and sneezes the pa-
`tients used the following scale to rate the number (and
`severity) of their symptoms: 0 = none; l: 1
`to 3
`(mild); 2 = 4 to 6 (modest); 3 = 7 to 10 (moderate);
`4 = 11 to 15 (moderately severe); 5 = more than 15
`(severe).
`1 and 2 weeks of double-blind treatment,
`After
`patients returned to the study site for a physical and
`
`
`
`000002
`
`

`

`820 Ratner et al.
`
`J ALLERGY CLlN IMMUNOL
`NOVEMBER 1994
`
`TABLE I. Demographic and baseline characteristics
`
`Azelastine NS q.d.
`(n = 62)
`
`Azelastine NS b.i.d.
`(n = 63)
`
`Chlorpheniramine
`(n = 62)
`
`Placebo
`(n = 64)
`
`Age (yr)
`Mean
`
`Range
`Sex (%)
`Male
`Female
`
`Race (%)
`White
`Other
`
`Weight (lb)
`Mean
`
`Range
`Baseline
`Mean TSC
`Mean MSC
`
`35
`
`12-65
`
`47
`53
`
`95
`5
`
`158.7
`
`79-237
`
`18.2
`12.1
`
`39
`
`12-70
`
`68
`32
`
`97
`3
`
`175.5
`
`92-270
`
`18.8
`12.5
`
`39
`
`13-68
`
`52
`48
`
`98
`2
`
`160.8
`
`95.5-280
`
`18.4
`12.4
`
`39
`
`13-71
`
`52
`48
`
`97
`3
`
`163.5
`
`90-272.5
`
`18.6
`12.2
`
`nasal examination and a diary review. A follow-up
`evaluation was performed 1 week after completion or
`early discontinuation of double-blind therapy.
`The primary efficacy parameters consisted of the
`Total Symptom Complex (TSC) and MSC severity
`scores. In general, the TSC consists of the symptoms
`that are typically part of the rhinitis profile, and the
`MSC consists of those symptoms most dominant in the
`rhinitis
`symptom profile. Five individual
`symptom
`scores (runny nose,
`itchy nose, sneezing, nose blows,
`and watery eyes) were summed to form the MSC
`severity score and three additional symptoms (postnasal
`drip, cough, and itchy eyes/ear/throat/palate) were
`summed with the MSC to form the TSC severity score.
`The changes from baseline for the TSC and MSC
`severity scores were based on the daily average mean
`scores. For each evaluation period (at the end of weeks
`1 and 2 and at the end of study), the mean for all the
`morning individual rhinitis symptom scores and the
`mean for all the evening individual rhinitis symptom
`scores were calculated for the respective periods. The
`overall daily average was then calculated on the basis of
`the mean of the two means. The TSC and MSC severity
`scores were determined by summing the daily average
`severity scores for the appropriate individual rhinitis
`symptoms at baseline and at each evaluation period.
`Secondary efficacy parameters consisted of changes
`in individual symptoms, changes in the TSC severity
`score that included the additional symptom of stuffi-
`ness, the investigators’ and patients’ global evaluations,
`the investigators’ assessment of rhinitis symptoms, and
`nasal examination findings. Safety parameters consisted
`of physical examinations, measurements of vital signs
`and body weights, clinical laboratory assessments, and
`adverse experience reports.
`
`The study protocol was approved by a national
`institutional review board.
`
`Statistical analysis
`
`Previous azelastine investigations showed that 61
`patients per group would be sufficient
`to detect a
`difference of 45% between the azelastine mean change
`and placebo mean change for the TSC severity score
`with an alpha level of 0.05 and a power of 80%.
`The primary analysis was an intent-to-treat analysis,
`performed with all available patient-response data at
`each weekly evaluation period. In addition, an end-
`point analysis, based on each patient’s last daily average
`score during double-blind treatment carried forward,
`and an overall analysis, based on each patient’s average
`of all available responses during double-blind treat-
`ment, were also performed. The mean percent and
`mean absolute changes from baseline for the TSC and
`MSC severity scores were analyzed by analysis of covar-
`iance, incorporating effects of treatments, center, and
`their interaction plus the baseline as a eovariate. Un-
`derlying assumptions such as normality and homosce—
`dasticity of the analysis of covariance model were tested
`and met.
`
`Treatments were compared by use of two-tailed
`t tests, with the mean square error from the covariance
`analysis. Treatment differences for global evaluations
`(investigators’ and patients’) and changes in nasal ex-
`amination findings were analyzed by the Cochran-Man-
`tel-Haenszel test.
`
`Within each treatment group, the change from base-
`line after each week of double-blind treatment was
`
`calculated for vital signs, body weights, and laboratory
`parameters and analyzed by a two-tailed t test. Treat-
`ment group comparisons were based on an analysis of
`
`
`
`000003
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 94, NUMBER 5
`
`Ratner et al.
`
`821
`
`
`
`
`
`MeanPercentImprovement
`
`1 Azelastine NS Cl.d.
`50 1 Azelastine NS b.i.d.
`2 Chlorpheniramine
`I: Placebo
`
`
`
`Endpoint
`
`‘ P305 P309 0
`+.05<Ps.10 v rsug
`
`..
`:o
`Eo>
`En.
`E.-
`1:ll
`5.’to
`CL
`
`1 /-lzelastine NS ed.
`50 1 Azelastme NS b.i.d.
`I C hlorpheniramine
`A: Placebo
`
`&O
`
`30
`
`I0C
`
`§2 _. O Endpoint
`
`‘ P305 (versus placebo)
`
`FIG. 1. Mean percent improvement in the TSC severity
`scores during weeks 1 and 2 and at end point.
`
`FIG. 2. Mean percent improvement in the MSC severity
`scores during weeks 1 and 2 and at end point.
`
`variance, including effects of centers, treatments, and
`center-by-treatment interaction. The proportions of pa-
`tients with the most frequently reported individual
`adverse experiences were compared across the treat-
`ment groups by chi square tests. The level of signifi-
`cance for all tests was set atp = 0.05.
`
`RESULTS
`
`Two hundred fifty-one patients, ages 12 to 71
`years, satisfied the inclusion criteria and were
`randomized to double—blind treatment. One pa-
`tient, however, was lost to follow-up, and another
`patient withdrew before taking any double-blind
`medication. Thus data from 250 patients were
`avaialble for the analyses of safety, and data from
`249 patients were included in the analyses of
`efficacy. The patients were randomized in equal
`numbers to the four treatment groups, and, with
`the exception of a higher mean baseline body
`weight
`in the azelastine NS b.i.d. group, there
`were no significant differences among the treat-
`ment groups for
`the demographic parameters
`(Table I).
`All 251 patients met the study entry criterion of
`a minimum MSC severity score. There were no
`statistically significant differences
`among the
`treatment groups at baseline in the mean TSC
`and MSC values (Table I). The average daily
`pollen counts for each week during double—blind
`therapy were very high throughout the study pe-
`riod (21200 grains/m3).
`
`Primary efficacy parameters
`
`The mean percent improvement in the TSC and
`MSC severity scores for
`the active-treatment
`groups were superior to those for the placebo
`
`1 Azelastine NS q.d.
`50 1 Azelastine NS b.i.d.
`C Chlorpheniramine
`I1‘! Placebo
`
`J3O
`
`{.00
`
`
`
`
`MeanPercentImprovement—tNOO
`
`‘Total Sympom
`Complex
`
`Major Symptom
`Complex
`
`Total Symptom
`Complex with Stuftiness
`+.05<F'S.10 v rsus
`' Pg_o5 pacebo
`
`FIG. 3. The overall mean percent improvement in the TSC
`and MSC severity scores and in the TSC score including
`the additional symptom of stuffiness.
`
`1 and 2).
`group at each evaluation point (Figs.
`After 1 week of treatment,
`the mean percent
`improvements in the TSC and the MSC severity
`scores for the azelastine NS q.d. (20% for both
`scores) and azelastine NS b.i.d. (27% and 30%,
`respectively) groups were statistically significantly
`(p 5 0.05) greater than that observed for the
`placebo group (7% for both scores).
`During week 2, statistical significance versus
`placebo was maintained for the azelastine NS
`b.i.d. group for the MSC severity score (36%) and
`approached statistical significance (p s 0.10) for
`the TSC severity score (34%). The mean percent
`improvements for the azelastine NS q.d. group
`during week 2 exceeded those for placebo in the
`TSC and MSC severity scores but were not statis-
`tically significant.
`
`
`
`000004
`
`

`

`822 Ratner er a|,
`
`J ALLERGY CLIN IMMUNOL
`NOVEMBER ‘I994
`
`TABLE II. Contribution of the individual rhinitis symptoms to the MSC and TSC severity scores at
`baseline and end point
`
`Azelastine NS q.d. (n = 62)
`
`Azelastine NS b.i.d. (n = 63)
`
`Symptom
`
`Mean (°/o)
`baseline
`
`Mean (°/o)
`end point
`
`Percent
`improvement
`
`Mean (°/o)
`baseline
`
`Mean (°/o)
`end point
`
`Percent
`improvement
`
`Runny nose/sniffles
`Nose blows
`Sneezes
`Itchy nose
`Watery eyes
`MSC
`Itchy eyes/ears/throat/palate
`Cough
`Postnasal drip
`TSC
`
`2.80 (15.4)
`2.65 (14.5)
`2.45 (13.4)
`2.26 (12.4)
`1.96 (10.8)
`12.12 (66.5)
`2.48 (13.6)
`1.18 (6.5)
`2.45 (13.4)
`18.23 (100)
`
`2.06 (15.8)
`1.91 (14.6)
`1.78 (13.6)
`1.62 (12.4)
`1.38 (10.6)
`8.75 (66.9)
`1.62 (12.4)
`0.82 (6.3)
`1.88 (14.4)
`13.07 (100)
`
`26.4
`27.9
`27.3
`28.3
`29.5
`27.8
`30.2
`30.5
`23.2
`28.3
`
`2.84 (15.1)
`3.05 (16.2)
`2.55 (13.5)
`2.10 (11.2)
`1.95 (10.4)
`12.49 (66.4)
`2.38 (12.6)
`1.57 (8.3)
`2.38 (12.6)
`18.82 (100)
`
`1.87 (15.0)
`2.13 (17.1)
`1.72 (13.8)
`1.35 (10.9)
`1.03 (8.3)
`8.10 (65.2)
`1.48 (11.9)
`1.12 (9.0)
`1.73 (13.9)
`12.43 (100)
`
`34.2
`30.2
`32.5
`35.7
`47.2
`35.0
`37.8
`28.7
`27.3
`33.9
`
`For the end-point analysis, the mean percent
`improvements in the TSC and MSC severity
`scores,
`respectively, for the azelastine NS q.d.
`group (28% and 27%) and the azelastine NS b.i.d.
`group (32% and 34%) exceeded those for placebo
`(19% and 20%) and were statistically significant
`(vs placebo) for the azelastine NS b.i.d. group.
`Overall. when both treatment weeks were com-
`
`bined (Fig. 3), the mean percent improvements in
`the TSC (30%), MSC (32%), and TSC with stuffi-
`ness (28%) were statistically significant for the
`azelastine NS b.i.d. group versus placebo (12% to
`13%). For the azelastine NS q.d. group, the over-
`all mean percent improvement across both weeks
`was statistically significant for the TSC severity
`score (24%) and approached statistical signifi-
`cance for both the MSC severity score (23%) and
`TSC with stuffiness severity score (22%) versus
`placebo.
`Treatment with 12 mg of chlorpheniramine
`maleate also resulted in improvements in the TSC
`and MSC severity scores that were statistically
`significantly greater than those for placebo after
`each week of
`treatment, overall across both
`weeks. and for the end-point analysis.
`
`Secondary efficacy parameters
`
`Results of the analyses for the secondary effi—
`cacy variables were generally consist:ent with the
`pattern of therapeutic responses for the mean
`percent improvements in the TSC and MSC se-
`verity scores. Treatment with azelastine resulted
`in improvements in all individual symptoms of the
`TSC severity score. For both azelastine NS
`groups, the percentage of each symptom’s contri-
`
`bution to the total severity score at the end point
`of the study was similar to its percent: contribution
`at baseline (Table II). Therefore the magnitude
`of each symptom’s improvement for the azelastine
`NS q.d. and b.i.d. groups was proportional to its
`contribution to the TSC severity score at baseline.
`In addition, across both weeks of treatment,
`investigators rated a greater majority of patients
`in the azelastine NS b.i.d. group (84%; p s 0.05)
`and the azelastine NS q.d. group (73%) as thera-
`peutically improved when compared with patients
`in the placebo group (66%). A greater majority of
`patients in the azelastine NS q.d. and b.i.d. groups
`(86% and 82%,
`respectively) also rated their
`therapetic response as improved when compared
`with the placebo group (77%).
`
`Safety parameters
`
`There were no clinically meaningful within-
`group changes or betwcen—group differences for
`any of the treatment groups in vital signs and
`body weight. Pre— and posttreatment physical ex-
`amination results were unremarkable. There were
`
`no differences between the azelastine NS groups
`and the placebo group in the percentage of pa-
`tients who had a change in the nasal examination
`parameters (nasal secretion and turbinate mu-
`cosa). In addition, there were no meaningful be-
`tween—treatment differences in the pretreatment
`and end-of—treatment mean laboratory values for
`adult patients.
`Azelastine NS was well tolerated, and only two
`patients treated with azelastine (both from the
`azelastine NS b.i.d. treatment group) discontin-
`ued therapy because of an adverse experience
`
`
`
`000005
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 94, NUMBER 5
`
`Ratner et al.
`
`823
`
`TABLE III. Number and percent of subjects by treatment who reported treatment-emergent
`adverse experiences*
`
`Azelastine NS q.d.
`Azelastine NS b.i.d.
`
`(n= 62)
`(n: 63)
`
`Chlorpheniramine
`(n: 61)
`
`Placebo
`(n: 64)
`
`Headache
`Dry mouth
`Somnolence
`lnfluenze—like symptom
`Rhinitis
`Pharyngitis
`
`9 (14.5%)
`2 (3.2%)
`3 (4.8%)
`1 (1.6%)
`4 (6.5%)
`2 (3.2%)
`
`6 (9.5%)
`3 (4.8%)
`2 (3.2%)
`3 (4.8%)
`0
`1 (1.6%)
`
`7 (11.5%)
`2 (3.3%)
`3 (4.9%)
`0
`2 (3.3%)
`4 (6.6%)
`
`7 (10.9%)
`0
`0
`1 (1.6%)
`0
`1 (1.6%)
`
`*lncidence of adverse experiences was 4% or less in any treatment group.
`
`(dizziness in one, increased blood pressure in the
`other). The most frequently reported treatment-
`emergent adverse experiences are shown in Table
`III. The incidences of the adverse experiences in
`the azelastine groups were not statistically signifi-
`cant when compared with those for the placebo
`group.
`
`DISCUSSION
`
`Allergic rhinitis is a disease that manifests in a
`complex of many symptoms. Although a single
`symptom may predominate in any given indi-
`vidual,
`it is traditional and clinically rational to
`examine the impact of a drug on the complex of
`rhinitis symptoms as the best
`indicator of how
`patients are responding to the medication (treat-
`ment efficacy). Accordingly, the primary efficacy
`parameters were the MSC severity score, which
`consisted of the five symptoms that predominate
`the rhinitis symptom profile, and the TSC severity
`score, which consisted of the MSC severity score
`plus three additional
`rhinitis symptoms. With
`these symptom complexes, previous studies have
`shown that azelastine NS (2 sprays per nostril q.d.
`and b.i.d.) has a rapid onset of action within 1 to
`2 hours and a long-lasting duration of effect of 12
`to 24 hours.” ‘3
`
`The results of this long-term trial indicate that
`azelastine NS is effective long-term therapy for
`the treatment of patients with symptomatic SAR.
`Both azelastine groups demonstrated statistically
`significant
`improvements in the TSC and MSC
`severity scores after 1 week of treatment. The
`b.i.d.
`regimen was associated with statistically
`significant
`improvements in the MSC severity
`score in week 2 and showed a trend toward
`
`statistical significance in the TSC severity score in
`week 2. Although the q.d. regimen was not statis-
`tically significant in the second week of treatment,
`the improvements were greater than those for the
`
`placebo group. The b.i.d. regimen was associated
`with statistically significant improvements in the
`overall and end-point analyses for both the TSC
`and MSC severity scores. In the overall analysis,
`the q.d. group had statistically significant
`im-
`provements in the TSC severity score and showed
`a trend toward statistical significance in the MSC
`severity score. This clinical efficacy of azelastine
`NS in the treatment of symptomatic SAR was
`demonstrated during a season that had a pollen
`count higher than those generally observed with
`other seasonal pollens.
`For the TSC severity score including the ad-
`ditional symptom of stuffiness, both azelastine
`groups also demonstrted improvements from base-
`line that were greater than those for placebo after
`both weeks of
`treatment and in the overall
`
`and end-point analyses. The results for the TSC
`score and the TSC score including stuffiness were
`similar.
`
`Imporlantly, the improvements in the TSC and
`MSC severity scores were the consequence of
`improvements in all of the individual
`rhinitis
`symptoms of the severity scores rather than in
`only one or a few of the symptoms. As shown in
`Table II and described above, the magnitude of
`the effect on each symptom is proportional to its
`contribution to the total score at baseline. Be-
`
`cause allergen exposure affects patients differ-
`ently,
`it
`is beneficial for treatment
`to have a
`greater effect on the more intense symptoms than
`on the less intense symptoms. As shown by the
`absolute improvement scores, the effect of azelas-
`tine is greatest on those symptoms with the great-
`est contribution to the total score at baseline. It
`
`should be further noted that even though azelas-
`tine is applied topically (intranasally),
`it affects
`the systemic symptoms associated with the allergic
`disease in addition to the nasal symptoms.
`We cannot definitively explain how intranasally
`
`
`
`000006
`
`

`

`824 Ratner et al.
`
`J ALLERGY CLIN IMMUNOL
`NOVEMBER 1994
`
`administered azelastine improves eye symptoms.
`Although passage through the nasolacrimal duct
`is a possibility, a contributing systemic effect can-
`not be excluded. Plasma samples for the determi-
`nation of azelastine levels were not obtained in
`
`this study. Other studies have demonstrated that
`azelastine is present in plasma after intranasal
`administration, albeit at very low concentrations
`(data on file, Wallace Laboratories). It is possible
`that a systemic action of azelastine contributes to
`the favorable ocular effects seen in this and other
`studies.
`
`It is also possible that somnolence is the con-
`sequence of a systemic effect. Azelastine is not a
`“classical antihistamine,” and although it is not
`“nonsedating,” this side effect is a dose-related
`phenomenon. The incidence of somnolence with
`low doses of orally administered azelastine (0.5
`mg b.i.d.) approximates that observed with pla-
`cebo (data on file, Wallace Laboratories). There-
`fore we expected the incidence of somnolence
`associated with intranasally administered azelas-
`tine to be very low and not dissimilar to that for
`placebo. Also surprising is the complete absence
`of somnolence in the placebo group. This obser-
`vation is unusual for placebo-controlled trials in
`the population with allergic rhinitis.
`The objective of this study was to compare the
`efficacy and safety of two dosages of azelastine NS
`with placebo in the long-term treatment of patients
`with symptomatic SAR. The positive-control group
`served to validate the study design and to assure
`that the conditions of allergic rhinitis were truly
`present and responsive to therapy. Chlorphe-
`niramine maleate (Chlor—Trimeton R.epetabs, 12
`mg b.i.d.) was selected as the positive control be-
`cause of its widely recognized efficacy in the symp-
`tomatic relief of SAR. The study was not designed
`nor was sample size sufficient to allow a compari-
`son of the azelastine groups with the positive con-
`trol group. The purpose of the positive control
`group was accomplished; chlorpheniramine male-
`ate demonstrated statistically significant improve-
`ment in the TSC and MSC severity scores com-
`pared with placebo (Figs. 1, 2, and 3). The good
`response in the positive control group is likely a
`consequence of
`the dose of Chlor-Trimeton
`Repetabs (12 mg b.i.d., the highest dose consistent
`with its labeling) that was chosen for this study.
`Azelastine NS has advantages over presently
`available topically administered antiallergic medi-
`cations such as decongestants and corticosteroids.
`As a topically administered antiallergic medica-
`tion, azelastine NS demonstrated clinical activity
`
`without nasal mucosa] sensitization common to
`
`other topical antihistamines and, unlike topical
`decongestants, produced no rebound effect after
`discontinuation.” Adverse experiences such as
`epistaxis and nasal burning were few and were
`mild to moderate in severity. In addition, long-
`term administration of topical corticosteroids may
`result in the development of localized infections
`of the nose and pharynx,“ and use of excessive
`doses may suppress hypothalamic—pituitary—adre-
`nal function.“ This is not a concern with azelas-
`
`tine therapy. Use of azelastine over prolonged
`periods of time should not be limited by side
`effects caused by systemic absorption or by the
`direct nasal application.
`This study demonstrated that 2 sprays of azelas-
`tine administered q.d. and b.i.d. are effective
`dosage regimens; however, some patients receiv-
`ing 2 sprays of azelastine q.d. may require an
`increase in dosage to 2 sprays b.i.d. with pro-
`longed antigen exposure. Azelastine’s favorable
`safety profile combined with a very rapid onset
`and prolonged duration of action in the relief of
`rhinitis symptoms may provide advantages over
`currently used therapies for
`the treatment of
`allergic rhinitis.
`
`We thank Mr. Anup Dam for providing the statistical
`analyses and Mr. Michael Brockley for his assistance in
`preparation of this manuscript.
`
`REFERENCES
`
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`J ALLERGY CLIN IMMUNOL
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`
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