I.--
`
`I L-
`
`AND
`
`WESTON LIBRARY
`NOV 1 4 1994
`
`VOL. 94, NO 5
`
`In memoriam: Paul P. Van Arsdel, Jr., MD
`Elliott Middleton, Jr., and Philip S. Norman
`
`Effects of long-term use of high-dose inhaled steroids
`on bone density and calcium metabolism
`Louis-Philippe Boulet et al.
`
`Screening for sinus disease in patients with asthma:
`A computed tomography-controlled comparison of
`A-mode ultrasonography and standard radiography
`Rudolf Pfister et al.
`
`Distribution of airborne mouse allergen in a major
`mouse breeding facility John L. Ohman, Jr., et al.
`
`A double-blind, controlled trial to assess the safety and
`efficacy of azelastine nasal spray in seasonal allergic
`rhinitis Paul H. Ratner et al.
`
`Occupational asthma in a latex doll manufacturing plant
`Nicholas A. Orlan et al.
`
`Findings before the diagnosis of asthma in young adults
`Russell Dodge et al.
`
`Human FcERl-lgG and humanized anti-lgE monoclonal
`antibody MaE11 block passive sensitization of human
`and rhesus monkey lung Ricardo Saban et al.
`
`Inhibition of human T-cell responses to house dust mite
`allergens by a T-cell receptor peptide
`Elizabeth R. Jarman et al.
`
`,,
`NOVEMBER 1994
`
`Whole blood chemiluminescence as a systemic inflam(cid:173)
`matory parameter in asthma Susann A. S. Nordman and
`Peter W. Nyberg
`
`Analysis of induced sputum to examine the effects of
`prednisone on airway inflammation in asthmatic sub(cid:173)
`jects David M. Claman et al.
`
`Single oral dose of prednisone decreases leukotriene 8 4
`production by alveolar macrophages from patients with
`nocturnal asthma but not control subjects: Relationship
`to changes in cellular influx and FEV,
`Sally E. Wenzel et al.
`
`Cloning, expression, and primary structure of Metapen(cid:173)
`aeus ensis tropomyosin, the major heat-stable shrimp
`allergen Patrick S. C. Leung et al.
`
`Latex-induced dermal and pulmonary hypersensitivity in
`rabbits Kari E. Reijula et al.
`
`Passive transfer of cutaneous mosquito-bite hypersensi(cid:173)
`tivity by lgE anti-saliva antibodies
`Timo Reunala et al.
`
`Predictive values of cord blood lgE and cord blood lym(cid:173)
`phocyte responses to food antigens in allergic disorders
`during infancy Yuki Kobayashi et al.
`
`Regulation of allergen-specific immune responses by
`CD4 + CD45R + cells in patients with allergic contact
`dermatitis Constantin N. Baxevanis et al.
`
`Complete table of contents with page numbers listed on
`pages 5A through 11 A
`
`OFFICIAL PUBLICATION OF
`AMERICAN ACADEMY OF
`ALLERGY AND IMMUNOLOGY
`
`Published monthly by
`
`~-..,1 Mosby
`
`ISSN 0091-6749
`
`

`

`THE JOURNAL OF
`
`ALLERGY
`
`AND
`
`CLINICAL IMM'UNOLOGY
`~T~ Mosby
`
`NUMBER 5
`
`VOLUME 94
`
`Copyright© 1994 by Mosby-Year Book, Inc.
`
`CONTENTS
`November 1994
`
`In memoriam
`
`Paul P. Van Arsdel, Jr., MD
`
`Elliott Middleton, Jr., MD, and Philip S. Norman, MD
`
`Answers to September CME examination
`
`Bruce S. Bochner, MD
`
`Clinical aspects of allergic disease
`
`Effects of long-term use of high-dose inhaled steroids on bone
`density and calcium metabolism
`
`Louis-Philippe Boulet, MD, FRCP(C), Marie-Claude Giguere, BSc, Joanne Milot, BSc, and
`Jacques Brown, MD, FRCP(C), Quebec City, Quebec, Canada
`
`Screening for sinus disease in patients with asthma: A computed
`tomography-controlled comparison of A-mode ultrasonography
`and standard radiography
`
`Rudolf Pfister, MD, Mareus Li.itolf, MD, Andreas Schapowal, MD, Birgit Glatte, MD,
`Michael Schmitz, MD, and Guenter Menz. MD. Davos-Wolfgang and Chur, Switzerland
`
`Distribution of airborne mouse allergen in a major mouse
`breeding facility
`
`John L. Ohman, Jr., MD, Karol Hagberg, RNNP, Margare/1 R. MacDonald, BS,
`Robert R. Jones, Jr., BA, Beverly J. Paigen, PhD, and Julie B. Kacergis , BA, Boston, Mass. ,
`and Bar Harbor, Maine
`
`793
`
`796
`
`804
`
`810
`
`Contents continued on page 7 A
`
`Vol. 94, No. 5, November 1994. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOOY (ISSN 0091-6749) is published monthly, except
`semimonthly in January (thirteen issues per year), by Mosby- Year Book, Inc., 11830 Westline Industrial Drive, St. Louis, MO 63146-
`3318; phone 1-800-453-4351 or (314) 453-4351. Second class postage paid at St. Louis, Mo. , and additional mailing offices. POSTMASTER:
`Send change of address to THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOOY, 11830 Westline Industrial Drive, St. Louis, MO 63146-
`3318. Annual subscription rates for 1994: domestic, $96.00 for individuals and $182.00 for institutions. Printed in the U.S.A. Copyright
`© 1994 by Mosby-Year Book, Inc. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form
`or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without
`permission in writing from the publisher.
`
`November 1994
`
`Page 5A
`
`

`

`CONTENTS
`CONTINUED
`
`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, A11sti1i, ahd
`New Braunfels, Texas, and Princeton, N.J.
`
`Occupational asthma in a latex doll manufacturing plant
`Nicholas A. Orfan, MD, Roberta Reed, PhD, Mark S. Dykewicz, MD, Michael Ganz, MD, and
`Gerald B. Kolski, MD, PhD, Cooperstown, N.Y., St. Louis, Mo., Racine, Wis., and Upland, Pa.
`
`818
`
`826
`
`Respiratory pathophysiologic responses
`
`Findings before the diagnosis of asthma in young adults
`
`831
`
`Russell Dodge, MD, Martha G. Cline, MS, Michael D. Lebowitz, PltD, and
`Benjamin Burrows, MD, Tucson, Ariz
`
`Allergens, lgE, mediators, inflammatory mechanisms
`
`Human FcERl-lgG and humanized anti-lgE monoclonal antibody
`MaE11 block passive sensitization of human and rhesus
`monkey lung
`
`836
`
`Ricardo Saban, PhD, Mary Haak-Frendsclw, PhD, Matthew Zine, MS , John Ridgway, BS,
`Cornelia Gorman, PhD, Leonard G. Presta, PhD, Dale Bjorling, DVM, Marcia Saban, BS, and
`Paula Jardieu, PhD, Madison, Wis., and S. San Francisco, Calif.
`
`International surface mail
`
`Continued on page 9A
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`or service.
`
`J ALLERGY CUN IMMUNOL
`
`November 1994 Page 7A
`
`

`

`CONTENTS
`
`CONTINUED
`
`Inhibition of human T-cell responses to house dust mite allergens
`by a T-cell receptor peptide
`
`844
`
`Elizabeth R. Jarman, BSc, Catherine M. Hawrylowicz , PhD, Elizabeth Panagiotopolou, MD,
`Robyn E. O'Hehir, MD, PhD, and Jonathan R. Lamb, PhD, London, England
`
`Whole blood chemiluminescence as a systemic inflammatory
`parameter in asthma
`
`Susann A . S . Nordman, MD, and Peter W. Nyberg, MD, Mjiilbolsta, Finland
`
`Analysis of induced sputum to examine the effects of prednisone
`on airway inflammation in asthmatic subjects
`
`David M . Claman, MD, Homer A. Boushey, MD, Jane Liu, MD, Hofer Wong, MD, and
`John V. Fahy, MB, ChB, San Francisco, Calif.
`
`Single oral dose of prednisone decreases leukotriene 84 production
`by alveolar macrophages from patients with nocturnal asthma but
`not control subjects: Relationship to changes in cellular influx
`and FEV,
`
`Sally£. Wenzel, MD, John B . Trudeau, Jay Y. Westcott. PhD, William R . Beam, MD, and
`Richard J. Martin , MD, Denver, Colo.
`
`853
`
`861
`
`870
`
`Cloning, expression, and primary structure of Metapenaeus ensis
`tropomyosin, the major heat-stable shrimp allergen
`
`882
`
`Patrick S. C. Leung, PhD, Ka Hou Chu, PhD, Wing Kuen Chow, BS, A/tab Ansari, PhD,
`Claudiu I. Bandea, PhD, Hoi Shan Kwan, PhD, Stephen M. Nagy, BS, and
`M . Eric Gershwin, MD, Davis, Calif .. Shatin, Hong Kong, and Atlanta, Ga.
`
`Latex-induced dermal and pulmonary hypersensitivity in rabbits
`
`891
`
`Kari E . Reijula, MD, PhD, Kevin J. Kelly, MD, Viswanath P. Kump, PhD,
`Hongyung Choi, MD, Robert D. Bongard, BS, Christopher A . Dawson , PhD , and
`Jordan N . Fink, MD, Milwaukee, Wis. , and Helsinki, Finland
`
`Passive transfer of cutaneous mosquito-bite hypersensitivity by lgE
`anti-saliva antibodies
`
`902
`
`Timo Reunala, MD, Henrikki Brummer-Korvenkontio, MSc, Liisa Riisiinen, MD,
`Guido Fra11<;ois, DrSc, and Timo Palosuo, MD, Helsinki and Tampere, Finland, and
`Antwerpen, Belgium
`
`Immunodeficiency and other clinical immunology
`
`Predictive values of cord blood lgE and cord blood lymphocyte
`responses to food antigens in allergic disorders during infancy
`
`Yuki Kobayashi, MD, Naomi Kondo, MD, Shinji Shinoda, MD, Hiroatsu Agata, MD.
`Osamu Fukutomi, MD, and Tadao Orii, MD , Gifu, Japan
`
`Regulation of allergen-specific immune responses by CD4+
`CD45R + cells in patients with allergic contact dermatitis
`
`Constantin N . Baxevanis, PhD , Nikolaos G. Papadopoulos, MD,
`Alexandra Katsarou-Katsari, MD . and Michael Papamichail, MD, Athens, Greece
`
`907
`
`917
`
`J ALLERGY CLIN IMMUNOL
`
`Continued on page I IA
`November 1994 Page 9A
`
`

`

`CONTENTS
`CONTINUED
`
`Brief communications
`
`Bronchial asthma, rhinoconjunctivitis, and contact dermatitis
`caused by onion
`Rommel Valdivieso, MD, Javier S11/,iza, MD. Susana Varela-Losada, MD, Jose Luis Su/,iza. MD .
`Maria Jose Nargwres, MD, Co11s11elo Martinez-Cocera. MD, a/Ill Martha Cabrera, MD ,
`Madrid, Spain
`
`Oral all_ergy syndrome in a subject with a highly relevant
`monosensitization to egg
`Gennaro Liccardi, MD, and Gennaro D'Amu/o, MD, Naples, Italy
`
`928
`
`931
`
`Instructions to authors on pages 20A-22A
`
`Newsview-American Academy of Allergy and Immunology on page 26A
`
`CME calendar-American Academy of Allergy and Immunology on page 34A
`
`Professional opportunities on page 62A
`
`The JOURNAL is abstracted and/or indexed in Index Medicus. Scie11ce Citation Index, Current Cmztell/s! Clinical Medicine, Current
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`
`J ALLERGY CUN IMMUNOL
`
`November 1994
`
`Page 11A
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`A double-blind, controlled trial to assess the
`safety and efficacy of azelastine nasal spray in
`seasonal allergic rhin itis
`
`Paul H. Ratner, MD,8 Steven R. Findlay, MD,b Frank Hampel, Jr., MD,C
`Julius van Bavel, MD/ Michael D. Widlitz, MD,e and
`Jeffrey J. Freitag, MDe
`San Antonio, Austin, and New Braunfels, Texas, and Princeton, N.J
`
`Background: Azelastine solution is a topically (nasal) administered antiallergy drug with a
`pre.clinical profile suggestive of efficacy in patients with allergic rhinitis.
`Objectives: The study was designed to compare the effectiveness and safety of two dosages of
`azelastine nasal spray (2 sprays per nostril once daily and twice daily) with that of placebo
`in the treatment" of patients 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 efficacy 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 ~ 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 efficacy and safety of azelastine nasal spray in the
`treatment of seasonal allergic rhinitis. (J ALLERGY CuN lMMUNOL 1994;94:818-25.)
`Key words: Azelastine nasal spray, symptomatic seasonal allergic rhinitis, Major Symptom
`Comple.x, Total Symptom Comple.x
`
`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, 1• 2 leu(cid:173)
`kotrienes, 3 • 4 T AME-esterase, 5 acetylcholine, 6 se-
`
`Abbreviations used:
`b.i.d.: Twice a day
`MSC: Major Symptom Complex
`NS: Nasal spray
`q.d.: Once a day
`SAR: Seasonal allergic rhinitis
`TSC: Total Symptom Complex
`
`From "Sylvana Research, San Antonio; bFindlay Research
`Associates, Inc., Austin; cPrivate practice, New Braunfels;
`dAilergy Associates of the Austin Diagnostic Clinic; and
`'Wallace Laboratories, Princeton.
`Supported by a grant from Wallace Laboratories, a Division of
`Carter-Wallace, Inc., Cranbury, N.J.
`Received for publication July 7, 1993; revised Apr. 19, 1994;
`accepted for publication May 12, 1994.
`Reprint requests: Paul H. Ratner, MD, Sylvana Research,
`7711 Louis Pasteur, Suite 406, San Antonio, TX 78229.
`Copyright © 1994 by Mosby-Year Book, Inc.
`0091-6749/94 $3.00 + 0 1/1/57589
`818
`
`rotonin,'· 8 and bradykinin. 9 The effects of inhib(cid:173)
`iting these mediators include the inhibition of
`allergic reactions, interference with inflammatory
`processes, and modulation of aiiway smooth
`muscle response. For these reasons, azelastine
`should be characterized as a multifunctional an(cid:173)
`tlallergic medication because it provide signifi(cid:173)
`cant therapeutic activity in allergic bayfever and
`allergic asthma. 10
`
`

`

`J ALLERGY CUN IMMUNOL
`VOLUME 94, NUMBER 5
`
`Ratner et al. 819
`
`Previous short-term studies of azelastine nasal
`spray (Astelin NS) have shown that dosage regi(cid:173)
`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
`12 These studies also demon(cid:173)
`rhinitis (SAR).11
`•
`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(cid:173)
`tions. In the winter months, the pollen from the
`mountain cedar blows in with "northern fronts"
`and is the only pollen present in significant
`amounts in the air during this time. Mountain
`cedar pollen counts are higher than those ob(cid:173)
`served with any other seasonal pollen. As such, it
`provides an excellent research model with which
`to evaluate the efficacy of medications in treat(cid:173)
`ment of pollen-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(cid:173)
`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(cid:173)
`trance or if they ·had a history of exercise-induced
`asthma and had used a !3-agonist inhaler only in con(cid:173)
`junction with exercise. Patients with acute exacerba(cid:173)
`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(cid:173)
`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(cid:173)
`molyn, 13-blockers, reserpine, or monoamine oxidase
`inhibitors within 14 days; Hi-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(cid:173)
`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(cid:173)
`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
`2 = modest,
`noticeable;
`symptoms
`noticeable;
`3 = moderate, somewhat bothersome; 4 = moderately
`severe, interfered with activities; and 5 = severe, con(cid:173)
`stant distraction. For nose blows and sneezes the pa(cid:173)
`tients used the following scale to rate the number ( and
`severity) of their symptoms: 0 = none; 1 = 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).
`After 1 and 2 weeks of double-blind treatment,
`patients returned to the study site for a physical and
`
`

`

`820 Ratner et al.
`
`J ALLERGY CUN 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(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`iance, incorporating effects of treatments, center, and
`their interaction plus the baseline as a covariate. Un(cid:173)
`derlying assumptions such as normality and homosce(cid:173)
`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(cid:173)
`amination findings were analyzed by the Cochran-Man(cid:173)
`tel-Haenszel test.
`Within each treatment group, the change from base(cid:173)
`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(cid:173)
`ment group comparisons were based on an analysis of
`
`

`

`J ALLERGY CUN IMMUNOL
`VOLUME 94, NUMBER 5
`
`Ratner et al. 821
`
`Azelastme NS Q ••
`-
`Azelastine NS b.l.d.
`50 -
`Chlorpheniramine
`=PlacebO
`
`c .,
`
`I C.
`
`.5 30
`c
`8
`&'. 20
`C: "' .,
`::!i 1
`
`Azo!asllne NS Q.d.
`-
`Azelasllne NS b.l.d.
`50 -
`=Placebo
`
`= Chlorphenlramine
`
`fil
`E 40
`~ e C.
`§ 3
`c
`8
`~ 20
`D..
`C: m
`::!i 10
`
`Week 2
`
`Endpoint
`
`+ .05<PS.1 O}v~rsu.s
`• PS.OS ptaceoo
`
`Endpoint
`• Ps.05 (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(cid:173)
`tients with the most frequently reported individual
`adverse experiences were compared across the treat(cid:173)
`ment groups by chi square tests. The level of signifi(cid:173)
`cance for all tests was set at p = 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(cid:173)
`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(cid:173)
`ment groups for the demographic parameters
`(TabJe I).
`All 251 patients met the study entry criterion of
`a minimum MSC severity score. There were no
`the
`statistically significant differences among
`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(cid:173)
`riod (:::: 1200 grains/m3
`
`).
`
`Primary efficacy parameters
`The mean percent improvement in the TSC and
`the active-treatment
`MSC severity scores for
`groups were superior to those for the placebo
`
`-Azelasline NS Q.d.
`50 -Azelasline NS b.i.d.
`
`= Chlorpheniramine
`
`=Placebo
`
`0
`
`Total Symptom
`Complex with Stuffiness
`+ .OS<Ps.1 o} verau.s
`• PS.OS placeoo
`
`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.
`
`group at each evaluation point (Figs. 1 and 2).
`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 :5 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(cid:173)
`tically significant.
`
`

`

`822 Ratner et al.
`
`J ALLERGY CUN IMMUNOL
`NOVEMBER 1994
`
`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(%)
`baseline
`
`Mean(%)
`end point
`
`Percent
`improvement
`
`Mean(%)
`baseline
`
`Mean(%)
`end point
`
`Percent
`improvement
`
`2.06 (15.8)
`2.80 (15.4)
`Runny nose/sniffles
`1.91 (14.6)
`2.65 (14.5)
`Nose blows
`1.78 (13.6)
`2.45 (13.4)
`Sneezes
`1.62 (12.4)
`2.26 (12.4)
`Itchy nose
`1.38 (10.6)
`1.96 (10.8)
`Watery eyes
`8.75 (66.9)
`12.12 (66.5)
`MSC
`1.62 (12.4)
`Itchy eyes/cars/throat/palate 2.48 (13.6)
`0.82 (6.3)
`1.18 (6.5)
`Cough
`2.45 (13.4)
`1.88 (14.4)
`Postnasal drip
`18.23 (100) 13.07 (100)
`TSC
`
`26.4
`27.9
`27.3
`28.3
`29.5
`27.8
`30.2
`30.5
`23.2
`28.3
`
`2.84 (15.1)
`1.87 (15.0)
`2.13 (17.1)
`3.05 (16.2)
`1.72 (13.8)
`2.55 (13.5)
`1.35 (10.9)
`2.10 (11.2)
`1.03 (8.3)
`1.95 (10.4)
`12.49 ( 66.4)
`8.10 (65.2)
`1.48 (11.9)
`2.38 (12.6)
`1.12 (9.0)
`1.57 (8.3)
`1.73 (13.9)
`2.38 (12.6)
`18.82 (100) 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(cid:173)
`bined (Fig. 3), the mean percent improvements in
`the TSC (30% ), MSC (32% ), and TSC with stuffi(cid:173)
`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(cid:173)
`all mean percent improvement across both weeks
`was statistically significant for the TSC severity
`score (24%) and approached statistical signifi(cid:173)
`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(cid:173)
`cacy variables were generally consistent with the
`pattern of therapeutic responses for the mean
`percent improvements in the TSC and MSC se(cid:173)
`verity scores. Treatment with azelastine re