ANNALS OF
`~LLERGY, ASTHMA, ~
`I MUNOLOGY
`
`June, 1999
`Volume 82, Number 6
`
`JUN 2 4 1999
`J5t llU CL,·:::: .. ,,. ~t:it:11CtS CHITF.H
`' " ~.,~l
`600 HIGHLANu Ali-MAUISON u,1 ,.: . ..
`
`Guest Editorial
`Physician Leadership in the New Millennium William E Berger, MD, MBA
`
`Review Article
`Antifungals in the Treatment of Allergic Bronchopulmonary Aspergillosis
`Eddie E Leon, MS and Timothy J Craig, DO
`
`Original Articles
`A Six-Month, Placebo-Controlled Comparison of the Safety and Efficacy of Salmeterol
`or Beclomethasone for Persistent Asthma Robert A Nathan, MD;
`Jacob L Pinnas, MD; Howard J Schwartz, MD; Jay Grossman, MD;
`Steven W Yancey, MS; Amanda H Emmett, MS; and Kathleen A Rickard, MD
`Asthma, Mite Sensitization, and Sleeping in Bunks Pere Gaig, MD;
`Ernesto Enrique, MD; Pilar Garcfa-Ortega, MD; Montserrat Olona, MD;
`Maria del Mar San Miguel, MD; and Cristobal Richart, MD
`Double-Blind Trials of Azelastine Nasal Spray Monotherapy Versus Combination
`Therapy with Loratadine Tablets and Beclomethasone Nasal Spray in Patients
`with Seasonal Allergic Rhinitis William E Berger, MD, MBA;
`Stanley M Fineman, MD; Phillip Lieberman, MD; Robert M Miles, MD; and
`the Rhinitis Study Groups
`A Summary of the Atmospheric Surveys Published in the United States Allergy
`Literature, 1966-1996 David A Frenz, Laura W Murray, and Adrienne A Boire
`Prevention of Exercised-Induced Asthma by a Natural Isomer Mixture of JI-Carotene
`lttai Neuman, MD; Hermona Nahum, MSc; and Ami Ben-Amotz, PhD
`Risk Factors for Acetaminophen and Nimesulide Intolerance in Patients with NSAID(cid:173)
`lnduced Skin Disorders Riccardo Asero, MD
`Relationship Between Induced Sputum Cell Counts and Fluid-Phase Eosinophil
`Cationic Protein and Clinical or Physiologic Profiles in Mild Asthma V Gutierrez,
`L Prieto, V Torres, R Trenor, C Perez, J M Berto, and J Marin
`Immediate Hypersensitivity in Adults with lgG Deficiency and Recurrent Respiratory
`Infections Valentin Popa, MD and Stephen M Nagy, Jr, MD
`Exercise-Induced Hyperventilation: a Pseudoasthma Syndrome Abdel-Hai Hammo, MD
`and Miles M Weinberger, MD
`
`{Complete Table of Contents appears on page A-2)
`
`Next Annual Meeting: November 12-17, 1999, Chicago, lllinios
`Official Publication of the American College of Allergy, Asthma & Immunology
`
`

`

`ANNALS OF
`ALLERGY, ASTHMA,&..
`IMMUNOLOGY
`
`Formerly published as ANNALS OF ALLERGY
`Contents of ANNALS OF ALLERGY, ASTHMA, &
`IMMUNOLOGY Copyright© 1999 by the American
`College of Allergy, Asthma, & Immunology.
`
`Editor: Edward J O'Connell, MD
`Mayo Clinic
`411 Guggenheim Bldg
`200 First St SW
`Rochester, MN 55905
`507-538-0009
`
`The Annals of Allergy, Asthma, &
`Immunology is the Official Publication
`of the American College of Allergy,
`Asthma, & Immunology. It is published
`monthly by the American College of
`Allergy, Asthma, & Immunology
`June, 1999
`
`GUEST EDITORIAL
`
`Physician Leadership in the New Millennium
`
`William E Berger, MD, MBA. . . . . . . . . . . . . . . . . . . . . . . . . . . 507
`
`REVIEW ARTICLE
`
`Eddie E Leon, MS and
`Antifungals in the Treatment of Allergic Bronchopulmonary Aspergillosis
`Timothy J Ciaig, DO.............................................. . ......................... .. .. 511
`
`ORIGINAL ARTICLES
`A Six-Month, Placebo-Controlled Comparison of the Safety and Efficacy of Salmeterol or
`Robert A Nathan, MD; Jacob L Pinnas, MD;
`Beclomethasone for Persistent Asthma
`Howard J Schwartz, MD; Jay Grossman, MD; Steven W Yancey, MS; Amanda H Emmett, MS; and
`Kathleen A Rickard, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
`
`Pere Gaig, MD; Ernesto Enrique, MD;
`Asthma, Mite Sensitization, and Sleeping in Bunks
`Pilar Garcfa-Ortega, MD; Montserrat Olona, MD; Marfa del Mar San Miguel, MD; and
`Cristobal Richart, MD. . ....... . ........ . .......................... . .................... ... . ..... 531
`
`Double-Blind Trials of Azelastine Nasal Spray Monotherapy Versus Combination Therapy with
`Loratadine Tablets and Beclomethasone Nasal Spray in Patients with Seasonal Allergic Rhinitis
`William E Berger, MD, MBA; Stanley M Fineman, MD; Phillip Lieberman, MD; Robert M Miles, MD; and
`the Rhinitis Study Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
`
`A Summary of the Atmospheric Surveys Published in the United States Allergy Literature, 1966-1996
`David A Frenz, Laura W Murray, and Adrienne A Boire ................. . ......... -. . . . . . . . . . . . . . . . . . 543
`
`Prevention of Exercise-Induced Asthma by a Natural Isomer Mixture of /3-Carotene
`lttai Neuman, MD; Hermona Nahum, MSc; and Ami Ben-Amotz, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
`
`. (Continued on page A-4)
`
`For submission of articles, see "Instructions for Authors"
`Changes of address directed
`to the ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
`should be sent to:
`Jim Slawny, Executive Director
`ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
`Suite 550, 85 West Algonquin Road, Arlington Heights
`Illinois 60005
`(847) 427-1200
`Telephone -
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`
`Annals of Allergy, Asthma, & Immunology (ISSN-1081-
`1206) is published monthly for $50.00 (US), $75.00 (US
`institutions) and $78.00 (fOreign) by the American Col(cid:173)
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`
`A-2
`
`

`

`(Continued from page A-2)
`
`Risk Factors for Acetaminophen and Nimesulide Intolerance in Patients with NSAID-lnduced Skin
`Riccardo Asero, MD ............ . ........ .. ................ . .... .. .... :.......... .. 554
`Disorders
`
`Relationship Between Induced Sputum Cell Counts and Fluid-Phase Eosinophil Cationic Protein and
`V Gutierrez, L Prieto, V Torres, R Trenor, C Perez,
`Clinical or Physiologic Profiles in Mild Asthma
`J M Berto, and J Marin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
`
`Immediate Hypersensitivity in Adults with lgG Deficiency and Recurrent Respiratory Infections
`Valentin Pop-a, MD and Stephen M Nagy, Jr, MD. ..... . . . .. . . . .. .. . . . . . .. .. .. . . .. .. .. . . . . . .. . . . . .. 567
`
`Abdel-Hai Hammo, MD and
`Exercise-Induced Hyperventilation: a Pseudoasthma Syndrome
`Miles M Weinberger, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
`
`Expression of ICAM-1 on Conjunctiva! Epithelium and ECP in Tears and Serum from Children with
`Jae-Won Oh, MD; Jung-Chui Shin, MD; Se-Jin Jang, MD; and
`Allergic Conjunctivitis
`Ha-Baik Lee, MD...... . ..... . .... . ............ . . . . . ....................... . .................. . . 579
`
`Differences of Genetic Effects for the Development of Allergic Diseases in Two Cities of Japan
`Hiroatsu Agata, MD; Norito Kawakami, MD; Naomi Kondo, MD; Terue Hayashi, MD;
`Osamu Fukutomi, MD; Hiroyuki Shimizu, MD; and Tadao Orii, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
`
`Author Index to Abstracts Presented at the 55th Annual Meeting of the ACAAI, Philadelphia,
`Pennsylvania. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
`
`Author Index to Volume 82, 1998 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
`
`CME EXAMINATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
`
`CME EXAMINATION ANSWERS (Identification No 009-005) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
`
`CME EXAMINATION ANSWER SHEET.............. . ... . .. .. ..... . ... . . . . . .... . . . ... . . ...... . . . ... .. 519
`
`INSTRUCTIONS FOR AUTHORS.................... . . .. . . ....... .. .. .. .... .. . . . .. ... . .. . . . ......... A-7
`
`CLASSIFIED ADVERTISING. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530, 534, 542
`
`ERRATA ... . ...... .. ...... . .............. . ........... . . . . ... .. . . ...... . . . ..... . ....... .. .. .. . . .... 542
`
`LETTER TO THE EDITOR
`Possible Mechanism of Paracetamol Anaphylaxis ... . ... . .... . . .. .. . ... . ... . : . . . . . . . . . . . . . . . . . . . . . . . 591
`
`A-4
`
`

`

`pouble-blind trials of azelastine nasal spray
`onotherapy versus combination therapy with
`I ratadine tablets and beclomethasone nasal
`s ray in patients with seasonal allergic rhinitis
`
`William E Berger, MD, MBA*, Stanley M Fineman, MDt, Phillip Lieberman, MD:j:,
`Robert M Miles, MD§; arid the Rhinitis Study Groups1l
`
`Background: Azelastine hydrochloride is an H 1-receptor antagonist with anti(cid:173)
`inflammatory properties that is available in the US as Astelin Nasal Spray for the
`treatment of seasonal allergic rhinitis. The symptoms of seasonal allergic rhinitis can
`initially be treated with monotherapy using either an antihistamine or an intranasal
`corticosteroid. Patients whose symptoms do not respond adequately are often prescribed
`1 a combination of both an antihistamine and an intranasal corticosteroid.
`Objective: Three multicenter, randomized, double-blind studies were conducted
`to determine whether patients with moderate-to-severe symptoms of seasonal aller(cid:173)
`gic rhinitis who had responded inadequately to monotherapy with either an oral
`antihistamine or an intranasal corticosteroid, and who were candidates for combi(cid:173)
`nation therapy with both an oral antihistamine and an intranasal corticosteroid,
`could be effectively treated with azelastine nasal spray monotherapy.
`Methods: Following a 1- to 2-week washout period, patients were randomized to 7
`days of double-blind treatment with either azelastine nasal spray (2 sprays per nostril
`bid, 1.1 mg/day) monotherapy or combination therapy with oral loratadine (Claritin, one
`10-mg tablet/day) plus intranasal beclomethasone dipropionate rnonohydrate (Beconase
`AQ, 2 sprays per nostril bid, 336 µ,g/day) . Efficacy was determined at the end of the
`study by both a physician assessment of the need for additional anti-rhinitis medication
`and a patient global evaluation of therapeutic effectiveness. The three studies were
`conducted at 71 investigational sites during the 1998 spring allergy season. Three
`separate studies were conducted to verify the reproducibility of the new study design.
`Results: In all three studies a total of 1,070 patients were randomized to
`double-blind treatment. There were no statistically significant differences in the
`percentage of patients treated with azelastine nasal spray versus patients treated with
`a combination of loratadine tablets and beclomethasone nasal spray who did not
`require additional anti-rhinitis medication (32% to 45% and 39% to 46%, respec(cid:173)
`tively). The patient global evaluation indicated that 77% to 84% of the patients
`treated with azelastine nasal spray had symptomatic improvement and 85% to 90%
`of the patients treated with loratadine tablets and beclornethasone nasal spray had
`symptomatic improvement. The most commonly reported adverse experience with
`azelastine nasal spray was a transient aftertaste (8%), while the most commonly
`reported adverse experience with loratadine tablets and beclomethasone nasal spray
`in combination was headache (6%).
`Conclusions: Based on the percentage of patients not requiring additional anti(cid:173)
`rhinitis medication and the patient assessment of efficacy, azelastine nasal spray
`monotherapy was as effective as the combination of oral loratadine plus intranasal
`beclomethasone in treating moderate-to-severe symptoms of seasonal allergic rhinitis.
`Ann Allergy Asthma Immunol 1999;82:535- 54 1.
`
`' INTRODUCTION
`Azelastine hydrochloride, a phthalazi(cid:173)
`' none derivative, is a high-affinity his-
`
`tamine H 1-receptor antagonist' admin(cid:173)
`istered as a nasal spray for
`the
`treatment of seasonal allergic rhinitis.
`
`In addition to H 1-receptor antagonism,
`azelastine also affects cells and chem(cid:173)
`ical mediators of the inflammatory re(cid:173)
`sponse as shown in in vitro studies2- 7
`and in animal models of allergic in(cid:173)
`tlammation. 8- 10 In clinical trials in pa(cid:173)
`tients with seasonal allergic rhinitis,
`azelastine reduced levels of leukotri(cid:173)
`enes and kinins following nasal aller(cid:173)
`gen challenge" and downregulated in(cid:173)
`tercellular
`adhesion
`molecule- I
`(ICAM-1) expression while reducing
`eosinophil and neutrophil infiltration
`in both the early- and late-phase of the
`allergic response. 12
`
`* Southern California Research Center,
`26732 Crown Valley Parkway, Suite 361, Mis(cid:173)
`sion Viejo, California and Allergy and Asthma
`Associates, 27800 Medical Center, Suite 150,
`Mission Viejo, California; t Atlanta Allergy and
`Immunology Research Foundation, 790 Church,
`Suite 410, Marietta, Georgia; :j: 300 Walnut·
`Bend Road South, Cordova, Tennessee; § 1715
`Thomson Drive, Lynchburg, Virginia. 'II The
`members of the Rhinitis Study Groups are as
`follows: Study No. 1- J. Spencer Atwater Jr,
`Asheville, NC; James Baker, Portland, OR;
`Charles Banov, Charleston, SC; William Berger,
`Mission Viejo, CA; Robert Berkowitz, Atlanta,
`GA; David Bernstein, Cincinnati, OH; Don Buk(cid:173)
`stein, Madison, WI; Jim Christensen, Las Vegas,
`NV; David Cook, Walnut Creek, CA; Jonathen
`Corren, Los Angeles, CA; Peter Creticos, Balti(cid:173)
`more, MD; Ira Finegold, New York, NY; Stan(cid:173)
`ley Fineman, Atlanta, GA; Stanley Galant, Or(cid:173)
`ange, CA; Sherwin Gillman, Orange, CA; Elliot
`Ginchansky, Dallas, TX; Pinkus Goldberg, Indi(cid:173)
`anapolis, IN; Alan Goldsobel, San Jose, CA;
`Gary Gross, Dallas, TX; Philip Halverson, Min(cid:173)
`neapolis, MN; Paul Hannaway, Salem, MA;
`Melvin Haysman, Savannah, GA; Lewis Kanter,
`Camarillo, CA. Study No. 2- William Berger,
`Mission Viejo, CA; Richard Collins, Charlotte,
`NC; Thomas Flaim, Albany, NY; David Gos(cid:173)
`sage, Knoxville, TN; Frederic Kiechel, Lincoln,
`NE; Craig Laforce, Raleigh, NC; Bobby Lanier,
`
`VOLUME 82, JUNE, 1999
`
`535
`
`

`

`In United States clinical trials, 13- 17
`azelastine nasal spray, at a dosage of 2
`sprays per nostril bid (1.1 mg/day),
`was effective in the management of a
`complex of symptoms associated with
`seasonal allergic rhinitis, including rhi(cid:173)
`norrhea, sneezing, nasal pruritus, post(cid:173)
`nasal drip, and itchy and watery eyes.
`Many patients with nasal congestion
`also experienced improvement in this
`symptom, an effect not typically asso(cid:173)
`ciated with oral antihistamines. Onset
`and duration of action assessments 13
`14
`·
`showed that azelastine nasal spray im(cid:173)
`proved baseline symptom scores with(cid:173)
`in 1 to 3 hours, while other studies18
`suggested that improvements may be
`evident in less than 30 minutes in some
`patients. Transient aftertaste, head(cid:173)
`ache, somnolence, and nasal burning
`were the most commonly reported ad(cid:173)
`verse experiences with azelastine nasal
`spray, and there have been no serious
`
`Ft Worth, TX; Dennis Ledford, Tampa, FL; Wil(cid:173)
`liam Lumry, Dallas, TX; Lyndon Mansfield, El
`Paso, TX; Jonathan Matz, Baltimore, MD;
`Donald McNeil, Worthington, OH; J Allen
`Meadows, Montgomery, AL; Robert Miles,
`Lynchburg, VA; David Miller, North Dart(cid:173)
`mouth, MA; Don Mitchell, Jackson, MS; Wil(cid:173)
`liam Morgan, Glendale, AZ; Zev Munk, Hous(cid:173)
`ton, TX; Martin Murcek, Greensburg, PA;
`Harold Nelson, Denver, CO; Thomas Nilsson,
`Omaha, NE; Michael Noonan, Portland, OR;
`Andrew Pedinoff, Princeton, NJ; William
`Storms, Colorado Springs, CO. Study No.
`3-Jeffrey Adelglass, Dallas, TX; William
`Berger, Mission Viejo, CA; Fred Grogan, Cor(cid:173)
`dova, TN; Hobert Pence, Louisville, KY; Jacob
`Pinnas, Tucson, AZ; Bruce Frenner, San Diego,
`CA; Paul Ratner, San Antonio, TX; Robert
`Reisman, Williamsville, NY; Thomas Rosenberg,
`Wichita, KS; Eric Schenkel, Easton, PA; William
`Schoenwetter, Minneapolis, MN;
`Eugene
`Schwartz, Altamont Springs, FL; Nathan Segall,
`Atlanta, GA; Jay Selcow, Hartford, CT; Martin
`Sher, Largo, FL; Charles Siegel, Gladstone, MO;
`William Silvers, Englewood, CO; Mark Stein,
`North Palm Beach, FL; Stanislaus Ting, Las
`Cruces, NM; Ned Whitcomb, Carmichael, CA;
`John Winder, Sylvania, OH; Thomas Woehler,
`Houston, TX; Barry Zeffren, Glen Carbon, IL;
`Myron Zitt, North Babylon, NY.
`This research was funded by a grant from
`Wallace Laboratories, Division of Carter-Wal(cid:173)
`lace, Inc., Half Acre Road, Cranbury, New
`Jersey.
`Received for publication January 4, 1999.
`Accepted for publication in revised form
`March 30, 1999.
`
`adverse experiences associated with its
`use.
`An antihistamine alone or a nasal
`corticosteroid alone can be used as
`first-line therapy for the treatment of
`seasonal allergic rhinitis, and for those
`patients whose symptoms are not ade(cid:173)
`quately controlled by either treatment
`often a combination of both an antihis(cid:173)
`tamine with an intranasal corticoste(cid:173)
`roid is prescribed. Three multicenter,
`randomized, double-blind, parallel(cid:173)
`group studies were conducted to com(cid:173)
`pare the effectiveness of azelastine
`nasal spray monotherapy versus com(cid:173)
`bination therapy with beclomethasone
`nasal spray plus
`loratadine
`tablets
`in patients with moderate-to-severe
`symptoms of seasonal allergic rhinitis
`who had not adequately responded to
`monotherapy with either a nasal ste(cid:173)
`roid or an oral antihistamine and who
`would be considered candidates for
`combination therapy with a nasal ste(cid:173)
`roid and an oral antihistamine. Effi(cid:173)
`cacy was evaluated by (1) comparing
`the percentage of patients in each treat(cid:173)
`ment group not requiring additional
`anti-rhinitis therapy based on a physi(cid:173)
`cian assessment at the end of the dou(cid:173)
`ble-blind treatment period and (2)
`comparing the percentage of patients
`with symptomatic
`improvement in
`each treatment group based on a pa(cid:173)
`tient global rating of therapeutic effec(cid:173)
`tiveness.
`
`METHODS
`Patients
`All patients were 12 years of age or
`older with a documented history of
`seasonal allergic rhinitis. Each patient
`was currently being treated with a
`monotherapy regimen, either an oral
`antihistamine or a nasal steroid, and
`was considered by the investigator to
`be a candidate for combination therapy
`with an oral antihistamine plus a nasal
`steroid due to lack of adequate symp- •
`tom control. Female patients were non(cid:173)
`gravid, non-nursing, of non-childbear(cid:173)
`ing potential or, if of childbearing
`potential agreed not to become preg(cid:173)
`nant during the study. Sexually active
`females of childbearing potential were
`
`practicing an adequate method of birth
`control. Patients unable to use or tol(cid:173)
`erate nasal spray, patients with asthma,
`patients who were treated with any in(cid:173)
`vestigational drug within 30 days of
`enrollment into this study, and patients
`being treated with antidepressant drugs
`were excluded from participation. Pa(cid:173)
`tients were also excluded if they had an
`acute respiratory infection within 30
`days of the study or any clinically sig(cid:173)
`nificant acute or chronic illness. All
`patients signed a written informed con(cid:173)
`sent document before entering the
`study, and written con~ent of a parent
`or legal guardian was required for pa(cid:173)
`tients under the legal age of consent.
`
`Study Design
`The three studies were carried out dur(cid:173)
`ing the 1998 spring allergy season at
`71
`investigational sites distributed
`throughout
`the contiguous United
`States. These studies were randomized,
`double-blind, parallel-group trials con(cid:173)
`sisting of 1- to 2-week baseline wash(cid:173)
`out _period ( 1 week for patients being
`treated with an oral antihistamine and
`2 weeks for patients being treated with
`an intranasal steroid) followed by a
`7-day double-blind treatment period.
`Chlorpheniramine maleate (Chlor-Tri(cid:173)
`meton Tablets 4 mg) was permitted on
`an "as needed" basis for the treatment
`of seasonal allergic rhinitis symptoms
`during the baseline washout period;
`however, it was not permitted for 48
`hours before the patients were random(cid:173)
`ized to double-blind treatment.
`After the baseline washout period
`and prior to randomization, a physician
`assessment was made of the severity of
`including nose
`rhinitis symptoms,
`blows, sneezes
`ranuy nose/sniffles,
`itchy nos~, watery eyes, itchy eyes/
`ears, itchy throat/palate, cough post(cid:173)
`nasal drip, and nasal congestion. Pa(cid:173)
`tients who qualified for randomization
`to double-blind treatment had symp(cid:173)
`tom rating scores of at
`least 18
`(scale = 0 to 50) with at least three of
`the symptoms of moderate or greater
`intensity. For nose
`than moderate
`blows and sneezes the actual number
`of each per day were counted and
`scored according
`to
`the follov,dng
`
`536
`
`. ANNALS .OF ALLERGY, ASTHMA, & IMMUNOLOGY
`
`

`

`scale: 0 = none, 1 = a littJe 1-3), 2 =
`moderate (4-·6), 3 = quite a bit (7-
`10), -1- = severe (11- 15), and 5 = very
`severe (greater than 15). Runny nose/
`sniffles, itchy nose, watery eyes, itchy
`eyes/ears, itchy throat/palate, cough,
`vostnasal drip, and nasal conge ·tion
`were cored according to the foUowing
`scale: 0 = none, no symptoms; 1 = a
`Jiftle, very mild symptoms that are
`barely noticeable and do not interlere
`with any activity; 2 = moderate, mild
`symptoms that are noticeable and do
`·not interfere with any activity; 3 =
`quite a bit, symptoms that are bother(cid:173)
`some and interfere slightly with activ(cid:173)
`ity; 4 = severe, symptoms that are
`bothersome and
`interlere modestly
`with activity; and 5 = very severe,
`symptoms that are very bothersome
`and disabling.
`Randomized patients received dou(cid:173)
`ble-blind treatment for 7 days with ei(cid:173)
`ther azelastine nasal spray (Astelin Na(cid:173)
`sal Spray, Wallace Laboratories) 2
`sprays per nostril twice daily (1. 1 mg/
`day) and a placebo capsule each morn(cid:173)
`ing or beclomethasone dipropionate
`monohydrate nasal spray (Beconase
`AQ, Glaxo Wellcome Inc.) 2 sprays
`per nostril twice daily bid (336 mcg/
`day) and a capsule containing one
`10-mg
`loratadine
`tablet
`((::laritin,
`Schering Corporation) each morning.
`Dosages of study drugs were selected
`according to the manufacturers recom(cid:173)
`mendations listed in the product label(cid:173)
`ing for each drug.
`
`Bli11ding and Randomization
`Study medications were provided in
`kits that were opened only by the pa(cid:173)
`tient, not in the presence of a study
`investigators or coordinator, to ensure
`that the double-blind was maintained.
`Commercially packaged azelastine na(cid:173)
`sal spray was provided in polyethylene
`bottles fitted with a metered-dose
`spray pump and over-labeled to mask
`the product identity. Commercially
`r packaged beclomethasone nasal spray
`Was provided in amber glass bottles
`fitted with metering .atomiz;ing pumps
`and nasal adapters and over-labeled to
`Ill.ask the product identity. Capsules
`containing one 10-mg loratadine tablet
`
`were packaged in polyethylene bottles
`containing 10 capsules per bottle.
`Matching placebo capsules were pack(cid:173)
`aged in identically appearing bottles
`and contained 10 capsules. Patients
`were assigned to double-blind treat(cid:173)
`ment according to a computer-gener(cid:173)
`ated, random allocation scheme.
`
`Efficacy and Safety Variables
`The primary efficacy variable was the
`percentage of patients in each treat(cid:173)
`ment group who did not require addi(cid:173)
`tional anti-rhinitis therapy, as evalu(cid:173)
`ated by a physician assessment (either
`yes or no), at the end of the 7-day
`double-blind
`treatment period. The
`secondary efficacy variable was the
`percentage of patients in each treat(cid:173)
`ment group who improved during the
`double-blind period based on a patient
`global evaluation of therapeutic effec(cid:173)
`tiveness. The patient global evaluation
`recorded the degree of symptom im(cid:173)
`provement on the last day of treatment
`versus how they felt prior to receiving
`the first dose of study medication at the
`time of randomization using the fol(cid:173)
`lowing 5-point scale: +2 = much bet(cid:173)
`ter, near complete or complete symp(cid:173)
`tom relief; + 1 = a little better, mild(cid:173)
`to-moderate overall improvement in
`symptoms; 0 = no change, no symp(cid:173)
`tom relief; -1 = a little worse, mild(cid:173)
`to-moderate overall deterioration of
`symptoms; and - 2 = much worse,
`marked deterioration of symptoms.
`Assessments of "a little better" or
`"much better" were considered im(cid:173)
`provements.
`Safety was evaluated by the number
`of occurrences and percentage of pa(cid:173)
`tients reporting any adverse events that
`occurred during double-blind treat(cid:173)
`ment.
`
`Statistical Methods
`To determine the sample size, the fol(cid:173)
`lowing assumptions were made: 45%
`of the patients treated with azelastine
`nasal spray would require additional
`anti-rhinitis therapy at the end of the
`study compared with 30% of the pa(cid:173)
`tients treated with loratadine tablets
`plus beclomethasone nasal spray. Ap(cid:173)
`proximately 1 70 patients in each of the
`treatment groups would provide 80%
`power at a = 0.05 (two-sided test) to
`detect a 15% difference between treat(cid:173)
`ments.
`Demographic characteristics in the
`two treatment groups were compared
`using analysis of variance for continu(cid:173)
`ous variables and chi-square tests for
`categorical variables. The number and
`percentages of patients considered not
`to require additional anti-rhinitis treat(cid:173)
`ment were compared by Fisher's Exact
`test. The percentages of patients who
`improved based on global evaluation
`were compared by the chi-square test.
`The number of occurrences and the
`percentage of patients reporting each
`adverse experience were summarized
`descriptively.
`
`RESULTS
`Patient Disposition
`The three studies were conducted at 71
`investigational sites and included a to(cid:173)
`tal of 1,070 patients who were random(cid:173)
`ized to double-blind treatment. The
`number of sites for each of "the three
`studies and the number of patients ran(cid:173)
`domized by treatment group at each
`site are shown in Table 1. More than
`98% of the patients enrolled in each of
`the three studies completed the double(cid:173)
`blind treatment period (Table 2). Three
`patients treated with azelastine nasal
`
`Table 1. Number of Sites and Patients Randomized by Treatment Group
`
`Study No.
`
`No. of Sites
`
`Az NS
`
`Beclo NS+ L
`
`Total
`
`23
`1
`342
`169
`173
`362
`182
`24
`2
`180
`366
`24
`3
`183
`183
`532
`538
`1070
`71
`Total
`Az NS = azelastine nasal spray and Beclo NS + L = beclomethasone nasal spray plus
`loratadine tablets.
`
`VOLUME 82, JUNE, 1999
`
`537
`
`

`

`Table 2. Patient Disposition
`
`Status
`
`Study 1
`(N = 342)
`Beclo NS+ L
`
`Az NS
`
`Study 2
`(N = 362)
`Beclo NS+ L
`
`Study 3
`(N = 366)
`Beclo NS+ L
`
`Az NS
`
`Az NS
`
`Randomized
`Total discontinued and reasons:
`lntercurrent illness
`Protocol violation
`Withdrew consent
`Treatment failure
`Adverse experience
`Completed study
`Az NS = azelastine nasal spray and Beclo NS + L = beclomethasone nasal spray plus loratadine tablets.
`
`173
`3
`0
`2
`
`0
`0
`170
`
`169
`
`0
`0
`0
`0
`168
`
`182
`4
`0
`
`0
`
`2
`178
`
`180
`
`0
`0
`0
`0
`1
`179
`
`183
`3
`1
`1
`0
`0
`
`180
`
`183
`3
`
`0
`0
`1
`180
`
`spray discontinued the study because
`of an adverse experience (one due to
`sinusitis, one due to excessive sneez(cid:173)
`ing, and one due to an upper respira(cid:173)
`tory infection). Two patients treated
`tablets plus be(cid:173)
`loratadine
`with
`clomethasone nasal spray discontinued
`the study because of an adverse expe(cid:173)
`rience ( one due to a combination of
`vertigo, nausea, and chest discomfort
`and the other due to nasal burning).
`Demographic and Clinical
`Characteristics
`Patients in the three studies were com(cid:173)
`parable with regard to demographic
`(Table 3) and clinical (Table 4) char(cid:173)
`acte1istics at baseline. In all three stud(cid:173)
`ies, the percentage of females (57% to
`63%) was higher than males (37% to
`43%) and the majority of the patients
`were white (81 % to 90% ). The mean
`age of the patients was approximately
`
`Table 3. Demographic Characteristics
`
`35 years with a range of 12 to 80 years.
`On average, patients had a 14- to 16-
`year history of seasonal allergic rhini(cid:173)
`tis and had moderate-to-severe symp(cid:173)
`toms, as determined by baseline
`symptom scores that ranged from 18 to
`4 7 among patients treated with azelas(cid:173)
`tine nasal spray and from 18 to 48
`among patients treated with loratadine
`tablets plus beclomethasone nasal
`spray. More than 80% of the patients
`in each treatment group in each of the
`studies had a previous inadequate re(cid:173)
`sponse to therapy with an oral antihis(cid:173)
`tamine and 13% to 17% had a previous
`inadequate response to therapy with an
`intranasal corticosteroid.
`Efficacy
`The primary efficacy variable was the
`percentage of patients in each treat(cid:173)
`ment group who did not require addi(cid:173)
`tional anti-rhinitis therapy as deter-
`
`mined by physician assessment at the
`end of the 7-day double-blind treat(cid:173)
`ment period. In each of the three stud(cid:173)
`ies, the physician assessment demon(cid:173)
`that monotherapy with
`strated
`azelastine nasal spray was comparable
`in effectiveness to combination ther(cid:173)
`apy with loratadine tablets plus be(cid:173)
`clomethasone nasal spray in managing
`the symptoms of seasonal allergic rhi(cid:173)
`nitis. In each of the three studies (Ta(cid:173)
`ble 5), there were no statistically sig(cid:173)
`nificant differences in the percentage
`of patients treated with azelastine nasal
`spray (range: 32% to 45%) versus pa(cid:173)
`tients treated with loratadine tablets
`and beclomethasone nasal spray in
`combination (range: 39% to 46%) who
`did not require additional anti-rhinitis
`medication. A subset analysis based on
`prior medication use indicated that
`there were no significant differences
`
`Characteristic
`
`AzNS
`N = 173
`
`Beclo NS+ L
`N = 169
`
`Az NS
`N;::: 182
`
`Beclo NS+ L
`N = 180
`
`AzNS
`N = 183
`
`Beclo NS+ L
`N;::: 183
`
`Study 1
`
`Study 2
`
`Study 3
`
`38%
`62%
`
`81%
`11%
`8%
`
`41%
`59%
`
`87%
`4%
`9%
`
`Gender
`Male
`Female
`Race
`White
`Black
`Other
`Age (yr)
`36.2
`Mean
`34.6
`35.0
`36.0
`37.0
`35.5
`36.0
`34.0
`Median
`12-74
`12- 64
`12- 67
`12-80
`Range
`Az NS = azelastine nasal spray and Beclo NS + L = beclomethasone nasal spray plus loratadine tablets.
`
`37%
`63%
`
`88%
`7%
`5%
`
`43%
`57%
`
`90%
`4%
`6%
`
`43%
`57%
`
`83%
`5%
`12%
`
`34.9
`37.0
`12- 72
`
`38%
`62 %
`
`86 %
`6%
`8%
`
`34.8
`35.0
`12-75
`
`5 38
`
`ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY'
`
`

`

`Table 4. Baseline Clinical Characteristics
`
`Characteristic
`
`Study 1
`
`Study 2
`
`Study 3
`
`Az NS
`N = 173·
`
`Beclo NS+ L
`N = 169
`
`Az NS
`N = 182
`
`Beclo NS+ L
`N = 180
`
`Az NS
`N = 183
`
`Beclo NS+ L
`N = 183
`
`Rhinitis duration (yr)
`Mean
`Median
`Symptom score
`Mean
`Median
`Range
`Previous inadequate response to:
`Antihistamine
`82%
`Nasal steroid
`17%
`Other
`1%
`Az NS = azelastine nasal spray and Beclo NS + L = beclomethasone nasal spray plus loratadine tablets.
`
`16.2
`12.0
`
`27.5
`27.0
`18-47
`
`84%
`16%
`
`16.2
`11.0
`
`26.6
`26.0
`18-48
`
`87%
`13%
`
`16.9
`15.0
`
`27.0
`27.0
`18-47
`
`15.0
`11 .0
`
`26.2
`25.0
`18-47
`
`86%
`14%
`
`14.4
`10.0
`
`27.4
`27.0
`18-46
`
`85%
`13%
`2%
`
`14.8
`11.0
`
`26.9
`27.0
`18-42
`
`85%
`13%
`2%
`
`Table 5. Primary Efficacy Variable:
`Percentage of Patients Not Requiring
`Additional Therapy by Physician Evaluation
`
`Treatment
`
`Study Study Study
`1*
`2*
`3*
`
`Az NS
`36%
`45%
`32%
`Beclo NS + L
`46%
`46%
`39%
`Az NS = azelastine nasal spray and Beclo
`NS + L = beclomethasone nasal spray plus
`loratadine tablets.
`• No statistically significant differences be(cid:173)
`tween treatment groups.
`
`between treatment groups regarding
`the percentage of patients who did not
`require additional therapy regardless of
`whethe