ORIGINAL INVESTIGATION. Montelukast, a Once-Daily Leukotriene Receptor Antagonist, in the Treatment of Chronic Asthma

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1 ORIGINAL INVESTIGATION Montelukast, a Once-Daily Leukotriene Receptor Antagonist, in the Treatment of Chronic Asthma A Multicenter, Randomized, Double-blind Trial Theodore F. Reiss, MD; Paul Chervinsky, MD; Robert J. Dockhorn, MD; Sumiko Shingo, MS; Beth Seidenberg, MD; Thomas B. Edwards, MD; for the Montelukast Clinical Research Study Group Objectives: To determine the clinical effect of oral montelukast sodium, a leukotriene receptor antagonist, in asthmatic patients aged 15 years or more. Design: Randomized, multicenter, double-blind, placebocontrolled, parallel-group study. A 2-week, singleblind, placebo run-in period was followed by a 12- week, double-blind treatment period (montelukast sodium, 1 mg, or matching placebo, once daily at bedtime) and a 3-week, double-blind, washout period. Setting/Patients: Fifty clinical centers randomly allocated 681 patients with chronic, stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 5% to 85% of the predicted value, at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled -agonist administration, a minimal predefined level of daytime asthma symptoms, and inhaled -agonist use. Twenty-three percent of the patients used concomitant inhaled corticosteroids. Primary End Points: Forced expiratory volume in 1 second and daytime asthma symptoms. Results: Montelukast improved airway obstruction (forced expiratory volume in 1 second, morning and evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, as-needed -agonist use, nocturnal awakenings) (P.1 compared with placebo). Montelukast provided nearmaximal effect in these end points within the first day of treatment. Tolerance and rebound worsening of asthma did not occur. Montelukast improved outcome end points, including asthma exacerbations, asthma control days (P.1 compared with placebo), and decreased peripheral blood eosinophil counts (P.1 compared with placebo). The incidence of adverse events and discontinuations from therapy were similar in the montelukast and placebo groups. Conclusions: Montelukast, compared with placebo, significantly improved asthma control during a 12-week treatment period. Montelukast was generally well tolerated, with an adverse event profile comparable with that of placebo. Arch Intern Med. 1998;158: From the Departments of Pulmonary/Immunology (Drs Reiss and Seidenberg) and Biostatistics (Ms Shingo), Merck Research Laboratories, Rahway, NJ; NE Research Center, Inc, North Dartmouth, Mass (Dr Chervinsky); International Medical Technology Consultants Inc, Prairie Village, Kan (Dr Dockhorn); and Allergy and Asthma Center, Albany Medical Center, Albany, NY (Dr Edwards). A list of the members of the Montelukast Clinical Research Study Group is given on page ASTHMA IS a significant worldwide health problem, accounting for $4.2 billion of health care costs in the United States in Despite the development and institution of treatment guidelines, 2 asthma remains a costly clinical problem, with a continuous need for new, innovative treatments. Current therapies have limitations, including poor compliance (inhalers, dosage frequency) and side effects. 3 New, effective, well-tolerated oral therapies may have a substantial impact on the management of asthma. The role of the cysteinyl leukotrienes (leukotrienes C 4,D 4, and E 4 ) in asthma has been clearly established. These leukotrienes are produced and released from proinflammatory cells, including eosinophils and mast cells, and are at least 1 times more potent bronchoconstrictors than histamine or methacholine in normal and asthmatic subjects. 4 Theleukotrienesmediatemanyofthe pathophysiologicalprocessesassociatedwith asthma, including microvascular leakage, bronchoconstriction, andeosinophilrecruitmentintotheairways. 5 Agentsthatinterrupt theactionoftheleukotrienes(5-lipoxygenase inhibitors and leukotriene receptor antagonists) have demonstrated improvement of chronic asthma in clinical trials, thus providing evidence for their role in asthma. 6-9 Montelukast sodium is a potent and specific leukotriene receptor antagonist 1 that has been shown to have substantial blockade of airway leukotriene receptors 24 hours after oral dosing. 11 This long du Downloaded From: on 1/8/218

2 PATIENTS AND METHODS STUDY DESIGN This multicenter, randomized, double-blind, placebocontrolled, 3-period, parallel-group trial compared the clinical effect of oral montelukast sodium, 1 mg once daily at bedtime, and placebo. The study consisted of a 2-week, single-blind, placebo run-in period (period 1); a 12-week, double-blind, active treatment period (period 2); and a 3- week, double-blind, placebo washout period (period 3). Clinic visits occurred every 2 weeks during period 1 and every 3 weeks thereafter. The study was conducted at 5 study centers in the United States between October 21, 1994, and August 13, 1995; 681 patients were randomly assigned, according to a computer-generated allocation schedule, to receive either a film-coated tablet of montelukast sodium, 1 mg, or matching placebo. In period 3, a subset of patients was blindly switched from montelukast to placebo according to the computer-generated allocation schedule. Written informed consent approved by the respective institutional review boards was obtained from each patient. If the patient was younger than 18 years, consent was also obtained from the patient s parent or guardian. INCLUSION CRITERIA Healthy, nonsmoking patients (male and female), aged 15 years and older with at least 1 year of intermittent or persistent asthma symptoms, were enrolled. Female patients had a negative serum -human chorionic gonadotropin test at the prestudy visit. All patients used short-acting inhaled -agonists as needed to treat their asthma, and a percentage of patients (not to exceed 25%) were allowed concomitant inhaled corticosteroids at a constant dosage beginning at least 4 weeks before the prestudy visit. Patients with non life-threatening, clinically stable, concomitant diseases could be enrolled in the study. Patients were eligible for randomization if they had, on at least 2 of the 3 visits during period 1, a forced expiratory flow in 1 second (FEV 1 ) between 5% and 85% of the predicted value (after withholding -agonist for at least 6 hours) and an absolute increase in FEV 1 of at least 15%, 2 to 3 minutes after inhalation of -agonist. In addition, patients were required to have a minimum total 2- week daytime asthma symptom score of 64 (a maximum score of 336 was possible) and to have used a daily average of at least 1 puff of -agonist during period 1. Patients received a peak flow meter (Mini-Wright; Clement Clark, Columbus, Ohio) and a practice diary card at the prestudy visit. Patients who demonstrated competence withthe use of these instruments and the ability to perform reproducible spirometry at each clinic visit were eligible for period 2. EXCLUSION CRITERIA Active upper respiratory tract infection within 3 weeks, acute sinusdiseaserequiringantibiotictreatmentwithin1week,emergency department treatment for asthma within 1 month, or hospitalizationforasthmawithin3monthsbeforetheprestudy visit were study exclusions. Excluded medications included oral, inhaled(concomitantinhaledmedicationusewasallowed for a subset of patients), and parenteral corticosteroids within 1 month; cromolyn sodium, nedocromil sodium, terfenadine, and loratadine within 2 weeks; theophylline (oral and intravenous), -agonists(oralorlong-actinginhaled),andanticholinergicagentswithin1week; astemizolewithin3months; and immunotherapyinitiatedwithin6monthsbeforetheprestudy visit. Accordingtoastandardizedprotocol, oralcorticosteroids were allowed for treatment of worsening asthma during periods 2 and 3. Patients who required rescue during period 1, more than 2 rescues during periods 2 and 3, or change in immunotherapy were discontinued from the study. EVALUATIONS The FEV 1 and daytime asthma symptom score were prespecified as primary end points. Other prespecified end points were morning and evening peak expiratory flow rate (PEFR), daily use of inhaled short-acting as-needed agonist, nights per week with nocturnal awakenings, asthmaspecific quality of life, physician s and patient s global evaluations, change in peripheral blood eosinophil counts, and asthma outcome end points including episodes of worsening asthma (percentage of days with asthma exacerbations), use of rescue oral corticosteriods (percentage of patients), discontinuation because of worsening asthma (determined by whether additional asthma medications were required), and asthma control days. Spirometry was performed at each clinic visit between 6 and9 AM, approximately1to12hoursafterthepreviousdose of study medication and after -agonist and short-acting antihistamines had been withheld for at least 6 and 48 hours, respectively.patientsusinginhaledcorticosteroidswereinstructed to take the morning dose either an hour before or after a clinic visit. Thespirometrymeasurementswerecollectedwithastandardspirometer(Nellcor/Puritan-BennettPB1/PB11, Lendena, Kan) and transmitted via modem to a central spirometry quality control center, where the data were reviewed to ensure uniform adherence to American Thoracic Society standards of acceptability and reproducibility. 12 Continual per- ration of action distinguishes it from other leukotriene receptor antagonists. Dose-finding studies in adults have identified 1 mg once daily at bedtime as the minimal dose to achieve the maximal response with no doselimiting toxic effects. 9 The purpose of this 12-week clinical trial was to determine the effect of oral montelukast on asthma control end points (airway obstruction, patient-reported end points, and asthma outcomes) and to evaluate its safety and tolerability profile. RESULTS PATIENTS Six hundred eighty-one patients entered period 2, the double-blind treatment period; 48 were allocated to montelukast and 273 to placebo treatment (Figure 1). The patients enrolled were white (89%), African American (4.1%), and Hispanic (4.7%), with a similar distribution between treatment groups. Other baseline demographic character Downloaded From: on 1/8/218

3 formance feedback was given to clinical centers to maintain and enhance spirometry quality. The largest FEV 1 from a set of at least 3 maneuvers was the visit value. Airway reversibility was evaluated at each visit during period 1 and at predefined visits during periods 2 and 3. The daily diary card contained daytime asthma symptom and nighttime awakening scales, previously shown to have acceptable evaluative measurement properties. 13 The 4 daytime asthma symptom questions addressing the severity and bothersomeness of asthma symptoms (using a 7-point scale where indicates best and 6, worst) were combined into a mean daily score. Nighttime awakenings were evaluated by the response to a single question by means of a 4-point scale ( no awakenings to awake all night ). 13 The change in nocturnal awakenings was determined for the prespecified group of patients with 2 or more nights with awakenings per week during the run-in period. The PEFR was measured by the patient in the morning, on arising, and in the evening, at bedtime, before taking the studymedication. Thelargestof3measurementswasrecorded onthediarycard, andmeasurementsperformedwithin4hours of -agonist use were identified. The patients also recorded as-needed -agonist use during the day and at night, and oral corticosteroid rescue, visit to a physician s office, or hospitalization because of worsening asthma. At the completion of period2(week12), physiciansandpatientsindependentlyevaluated the change in the patient s asthma (global evaluations) by selecting the most appropriate response by means of a 7- point scale ( very much better, moderately better, a little better, unchanged, alittleworse, moderatelyworse, very much worse ). At the randomization visit (before patients received study medication) and at the end of period 2 (week 12), the patients also completed the validated Asthma Quality of Life Questionnaire. 14 The questionnaire contained 32 questions divided into 4 quality-of-life domains activity, symptoms,emotions,andenvironment withresponsesona7-point scale where indicates worst and 6, best. An asthma exacerbation day was defined as a day when any 1 of the following occurred: a decrease of more than 2% from baseline in morning PEFR, PEFR less than 18 L/min, an increase of more than 7% from baseline in -agonist use (aminimumincreaseof2puffs),anincreaseofmorethan5% frombaselineinsymptomscore, awakeallnight withasthma, or worsening asthma requiring oral corticosteroid rescue, visit to a physician s office, or hospitalization. An asthma control daywasdefinedasanydaywhennoneofthefollowingoccurred: worsening asthma requiring oral corticosteroid rescue, visit to a physician s office or hospitalization, nocturnal awakenings, or use of more than 2 puffs of -agonist. Blood samples were obtained before and 3, 6, 12, and 15 weeks after randomization to period 2. Clinical laboratory tests (ie, hematology, serum chemistry, and urinalysis) and blood eosinophil counts (determined by an automated cell counter in a central laboratory) were performed. Female patients had serum -human chorionic gonadotropin measured at the prestudy visit and either a serum or urine pregnancy test at each visit. A complete physical examination and 12-lead electrocardiogram were performed before and after randomization; vital signs were recorded at each visit. STATISTICAL METHODS The primary analysis was an intention-to-treat approach including all randomized patients with a baseline value and at least 1 treatment period measurement. The data were analyzed as averages during the treatment period, and data points were not carried forward. For end points analyzed as change or percentage change from baseline, the average period 1 measurement was the baseline value. The mean period 2 response was compared between treatment groups by means of an analysis of variance (ANOVA) model that included terms for treatment, inhaled corticosteroid use (stratum), and study center. The between-group differences of within-group change and the 95% confidence interval (CI) were computed on the basis of the ANOVA model. Quality of life and the global evaluations were analyzed by the ANOVA model. In addition, the 7 categories of the global evaluations were collapsed into 3 categories (better, no change, and worse) and analyzed with a Cochran-Mantel-Haenszel test to corroborate the ANOVA results. The presence of quantitative interactions between demographic subgroups and changes in the study end points were testedbytheanovamodel.interactionswereconsideredclinically significant if a demographic characteristic had a significantinteractionwithatleast2of4endpoints.correlationanalysis among baseline and changes in end point values (FEV 1 and daytime asthma symptoms) were also performed. Assumptions of normality and homoscedasticity were assessed. All statistical tests were 2 tailed, and P.5 was considered statistically significant. The safety evaluations included all randomized patients. The number and percentage of patients reporting clinical adverse experiences and laboratory abnormalities were summarized by treatment group. POWER AND SAMPLE SIZE The study was designed with a sample size of 3 and 2 patients for montelukast and placebo groups, respectively, to have 95% power to detect ( =.5, 2-tailed test) a mean difference between treatment groups of 5.4 percentage points in FEV 1 (percentage change from baseline) and 9.1% in daytime symptom score (change from baseline). istics were comparable between the montelukast and placebo groups (Table 1). Six hundred seven patients (89%) completed periods 2 and 3; the discontinuation rate was significantly (P.5) higher in the placebo (14.3%) than the montelukast (8.6%) group (Table 2). Five patients (2 and 3 in the montelukast and placebo groups, respectively) and 8 patients (4 in each treatment group) were excluded from the intention-to-treat analysis because of missing baseline or treatment period data for FEV 1 and daytime symptom score, respectively. EFFICACY Montelukast significantly improved (P.1 compared with placebo) airway obstruction, as shown by an increase in FEV 1 of 13.1% (placebo, 4.2%), in morning PEFR of 24. L/min (placebo, 4.6 L/min), and in evening PEFR of 15.9 L/min (placebo, 4.2 L/min). The mean difference compared with placebo, based on ANOVA, was 8.9% (95% CI, 6.8% to 11.%) for FEV 1, 19.4 L/min (95% CI, 14.2 to 24.5 L/min) for morning PEFR, and 11.6 L/min 1215 Downloaded From: on 1/8/218

4 12-wk Active Treatment 3-wk Washout Period 273 Patients Received Clinic Visits Every 3 wk 35 Patients (12.8%) Discontinued in Period Patients (87.2%) Completed Period 2 4 Patients (1.5%) Discontinued in Period Patients (85.7%) Completed Study 1515 Screened Patients 681 Patients Randomized After 2-wk Run-In 48 Patients Received Montelukast Sodium Clinic Visits Every 3 wk 31 Patients (7.5%) Discontinued in Period Patients (92.5%) Completed Period 2 Continued Montelukast 33 (8.8%) Switched to 47 (11.5%) Montelukast 4 (.1%) (%) Discontinued in Period 3 Montelukast 326 (79.9%) 47 (11.5%) Completed Study Figure 1. Study profile. Of the 1515 screened patients, 834 were not randomized; the most common reason was failure to meet the spirometry criteria. Patients were randomized to receive either oral montelukast sodium, 1 mg, or matching placebo. Approximately 89% of the patients completed the study. Asterisk indicates that the reasons for discontinuation are listed in Table 2. Table 1. Demographic and Baseline Characteristics: Randomized Patients* (n = 273) Montelukast Sodium, 1 mg (n = 48) Age, median (range) 31 (15-79) 31 (15-78) Duration of asthma, y 15 (.5-62) 16 (.5-64) median (range) Sex, % of patients Male Female Concomitant inhaled corticosteroids, % of patients History of exercise-induced asthma, % of patients History of allergic rhinitis, % of patients FEV 1, L 2.5 ± ±.7 FEV 1, % of predicted 68.5 ± ± 1.6 PEFR, L/min Morning 391 ± ± 88 Evening 421 ± ± 9 Daytime asthma 2.5 ± ±.8 symptom score ß-Agonist, puffs/d 5.3 ± ± 3.2 Nocturnal awakenings, nights/wk 4. ± ± 2.4 Quality of life score, 3.6 ± ±.9 pooled domains Eosinophils, 1 9 /L.31 ± ±.26 *Data are mean ± SD unless otherwise specified. FEV 1 indicates forced expiratory volume in 1 second; PEFR, peak expiratory flow rate. The daytime asthma symptom score was the average of the responses to 4 questions scored on a scale of to 6. Table 2. Reasons for Discontinuation During Periods 2 and 3 (n = 273) No. (%) Montelukast Sodium, 1 mg (n = 48) Clinical adverse experiences 12 (4.4) 9 (2.2) Positive pregnancy tests 1 (.4) 1 (.2) Withdrawal of consent 12 (4.4) 13 (3.2) Protocol deviations 9 (3.3) 6 (1.5) Unavailable for follow-up 5 (1.8) 6 (1.5) Total Discontinued 39 (14.3) 35 (8.6)* *P.5 compared with placebo. (95% CI, 6.9 to 16.3 L/min) for evening PEFR. The improvement observed in evening PEFR indicated that montelukast provided protection throughout the 24-hour dosing interval. Also, patient-reported end points, eg, daytime asthma symptoms and as-needed -agonist, were significantly (P.1 compared with placebo) improved by montelukast (Figure 2). Furthermore, patients reported significantly less nocturnal awakening ( 1.66 and.8 nights per week for montelukast and placebo, respectively); the mean difference, based on ANOVA, was.87 (95% CI, 1.22 to.53). The improvements observed in airway obstruction and patient-reported end points were maintained consistently throughout the 12-week treatment period 2 (Figure 2). The prespecified patient subgroup that was blindly switched from montelukast to placebo during period 3 showed the treatment effects returned toward, but not past, the placebo group, confirming the beneficial effects of montelukast, and withdrawal of montelukast did not cause rebound worsening of asthma (Figure 2). Within 1 day of dosing, montelukast achieved nearmaximal effect as shown by the response during the first 21 days of period 2. Figure 3 illustrates this rapid, beneficial response for -agonist use, daytime asthma symptoms, and morning PEFR. Similar improvements were seen in nocturnal awakenings and evening PEFR. In addition, each asthma-specific quality-of-life domain had significantly higher scores for patients treated with montelukast (P.1 compared with placebo) during the 12- week treatment period (Figure 4). Also, patients and physicians global evaluations demonstrated that patients receiving montelukast had significantly improved asthma control compared with patients receiving placebo (Figure 5). Patients treated with montelukast experienced fewer days with asthma exacerbations (a decrease of 31%) and more asthma control days (an increase of 37%) than patients receiving placebo (P.1) (Figure 6). Fewer patients (a decrease of 28%) treated with montelukast required oral corticosteroid rescues (6.9% compared with 9.6% for placebo; P=.2), and fewer patients (a decrease of 59.5%) discontinued therapy because of worsening asthma (1.5% compared with 3.7% for placebo; P=.7). Montelukast significantly decreased peripheral blood eosinophil counts (P.1 compared with placebo) (Figure 7). There was no correlation between the improvements in FEV 1 or daytime asthma symptom scores and patients baseline values. Furthermore, there were no clini Downloaded From: on 1/8/218

5 Morning FEV 1, % Change From Baseline β-agonist Use, % Change From Baseline Daytime Symptoms Score, Change From Baseline Washout Weeks in Active Treatment Morning PEFR, L/min Change From Baseline Washout Weeks in Active Treatment Figure 2. The effect of montelukast sodium and placebo on the 2 primary end points (forced expiratory volume in 1 second [FEV 1 ] and daytime asthma symptoms), morning peak expiratory flow rate (PEFR), and as-needed -agonist use during the 12-week, active treatment period and the 3-week, placebo washout period. The FEV 1 was measured at every visit; PEFR, daytime asthma symptoms, nocturnal awakenings, and as-needed -agonist were recorded daily by the patients. Montelukast, compared with placebo, caused significant ( P.1) improvements in all end points. The dashed line represents the patient subgroup switched to placebo in the placebo washout period. The values are reported as mean±se. Morning PEFR, L/min Change From Baseline Daytime Asthma Symptoms Score, Change From Baseline cally significant interactions between the prespecified subgroups of age, sex, race, history of allergic rhinitis, history of exercise-induced asthma, study center, and concomitant use of inhaled corticosteroid and these study end points. For example, patients taking concomitant inhaled corticosteroids had an increase in FEV 1 of 1.3% with montelukast (1.6% with placebo), and patients without corticosteroids had an increase in FEV 1 of 13.9% with montelukast (5.% with placebo). SAFETY The overall frequency of clinical adverse events reported by patients was similar between the montelukast and placebo groups. Upper respiratory tract infection and headache were the most frequently reported clinical adverse events, similar in incidence between treatments (Table 3). Twelve patients (4.4%) in the placebo group and 9 (2.2%) in the montelukast group discontinued treatment because of adverse experiences. Six of the 12 patients in the placebo group discontinued because of asthma, 2 because of bronchitis, and the other 4 because of depression, facial edema, endometriosis, and headache. Three of the 9 montelukast-treated patientsdiscontinuedtreatmentbecauseofasthma; theother 6 patients discontinued because of anxiety, depression, dyspnea, gastritis, back pain, and respiratory failure. There was no difference in the frequency of laboratory adverse events between the montelukast (7.1%) and placebo (5.5%) groups. The most frequently reported event was increased levels of alanine aminotransferase: 2.5% with montelukast and 1.5% with placebo treatment. Serum alanine and aspartate aminotransferase elevations more than β-agonist Use, % Change From Baseline Days in Active Treatment Figure 3. The effect of montelukast sodium and placebo during the first 21 days in the active treatment period. The values are reported as mean±se. PEFR indicates peak expiratory flow rate. 2 times above the upper limit of normal were infrequent in both the montelukast and placebo groups (.9% and 1.5%, respectively). Also rare (.7%), elevations of alkaline phosphatase and serum bilirubin levels were similar in incidence between treatment groups. Laboratory abnormalities either returned toward normal while study therapy was continued, or had explanations not related to study medications, such as weight-lifting and minor blunt trauma injuries. No laboratory adverse event caused discontinuation Downloaded From: on 1/8/218

6 .8 4 Score, Change From Baseline % of Days Activity Symptoms Emotions Environment Domains Asthma Exacerbation Days Asthma Control Days Figure 4. Asthma-specific quality of life score in the montelukast sodium and placebo groups. The values are reported as mean±se. Asterisk indicates P.1, montelukast compared with placebo. % of Patients % of Patients Better No Change Worse COMMENT Better No Change Worse Figure 5. Mean percentage of patients with specific responses to the patient (top) and physician (bottom) global evaluations. The - to 6-point scale was collapsed to 3 categories: better (, 1, and 2), no change (3), and worse (4, 5, and 6) for montelukast sodium and placebo. Treatment with montelukast sodium, compared with placebo, showed significant improvement ( P.1 with Cochran-Mantel-Haenszel test). This clinical trial demonstrates that montelukast provided clinical benefit during the 12-week treatment period by consistent and significant improvement of all asthma control variables compared with placebo. Montelukast improved airway obstruction, patient-reported end points, and asthma outcomes (protection against worsening asthma episodes), consistent with the goals of asthma therapy as outlined in the Global Initiative for Asthma. 2 Figure 6. Effect of montelukast sodium compared with placebo on asthma exacerbation and asthma control days during period 2. See Patients and Methods section for definition of the end points. The values are reported as percentage of total study days (mean±se). Asterisk indicates P.1, montelukast compared with placebo. Eosinophil Change From Baseline, 1 9 /L Weeks in Active Treatment Washout Figure 7. The effect of montelukast sodium on peripheral blood eosinophils during the active treatment period and washout period. The values are reported as mean±se change from baseline. P.1 compared with placebo during the 12-week treatment period. Table 3. Clinical Adverse Experiences Occurring in 6% or More of Patients in Either Treatment Group (n = 273) No. (%) Montelukast Sodium (n = 48) Headache 57 (2.9) 73 (17.9) Worsening asthma 32 (11.7) 46 (11.3) Upper respiratory tract infection 96 (35.2) 129 (31.6) Pharyngitis 29 (1.6) 22 (5.4) Sinusitis 22 (8.1) 31 (7.6) For each end point, the effect of montelukast was consistent throughout the double-blind treatment period (period 2), indicating that tolerance did not develop. Tolerance can be a clinical problem with some therapies, including receptor antagonists. 15,16 After 12 weeks of treatment, removal of montelukast did not cause rebound worsening of asthma in any end point. Rebound worsening on treatment discontinuation has been experienced with re Downloaded From: on 1/8/218

7 The Montelukast Clinical Research Study Group Leonard C. Altman, MD, Allergy Clinic, Pacific Medical Center, Seattle, Wash; George Bensch, MD, Stockton, Calif; William E. Berger, MD, Southern California Research Center, Mission Viejo, Calif; Jonathan A. Bernstein, MD, Bernstein Allergy Group, Inc, Cincinnati, Ohio; Kathryn Blake, PharmD, The Nemours Children s Clinic, Jacksonville, Fla; Milan L. Brandon, MD, California Research Foundation, San Diego, Calif; Edwin Bronsky, MD, AAAA Medical Research Group, Salt Lake City, Utah; Christopher Brown, MD, California Pacific Medical Center, San Francisco, Calif; William Busse, MD, University of Wisconsin, Madison; Paul Chervinsky, MD, New England Research Center, Inc, Allergy & Asthma Center, North Dartmouth, Mass; John J. Condemi, MD, Allergy, Asthma, Immunology of Rochester, PC, Rochester, NY; David L. Daniel, MD, Wenatchee Valley Clinic, Wenatchee, Wash; Robert J. Dockhorn, MD, International Med Tech Consultants, Inc, Prairie Village, Kan; Thomas B. Edwards, MD, Allergy and Asthma Center, Albany Medical Center, Albany, NY; Albert F. Finn, MD, Allergy and Asthma Center of Charleston, Pa, N Charleston, SC; Stanley J. Galant, MD, Orange, Calif; Marc F. Goldstein, MD, The Asthma Center, Philadelphia, Pa; Jay Grossman, MD, Allergy Care Consultants, Ltd, Tucson, Ariz; William G. Harris, MD, Magan Medical Clinic, Inc, Covina, Calif; Leslie Hendeles, PharmD, University of Florida, Health Science Center, Gainesville, Fla; Mani Kavuru, MD, Cleveland Clinic Foundation, Cleveland, Ohio; James P. Kemp, MD, Allergy and Asthma Medical Group and Research Center, San Diego; Philip E. Korenblat, MD, Barnes West County Hospital, The Asthma Center, St Louis, Mo; Michael Kramer, MD, Spokane Allergy and Asthma Clinic, Spokane, Wash; Craig LaForce, MD, North Carolina Clinical Research, Raleigh, NC; Thomas Littlejohn, MD, Piedmont Research Assoc, Winston-Salem, NC; Richard Lockey, MD, University of South Florida, Asthma, Allergy and Immunology, Clinical Research Unit, Tampa; Zev Munk, MD, Breco Research, Houston, Tex; Anjuli Seth Nayak, MD, Asthma and Allergy Associates, SC, Normal, Ill; Harold Nelson, MD, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colo; Michael J. Noonan, MD, Allergy Assoc, PC Research Center, Portland, Ore; Gregory Owens, MD, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pa; Stephen Park, MD, Daly City, Calif; David S. Pearlman, MD, Colorado Allergy and Asthma Clinic, PC, Aurora, Colo; Andrew Pedinoff, MD, Princeton Allergy & Associates, Princeton, NJ; Bruce Prenner, MD, Allergy Associates Medical Group, Inc, San Diego; Joan Reibman, MD, Bellevue Hospital/General Clinical Research Center, New York, NY; Alan Segal, MD, Allergy Associates Research, Dallas, Tex; James M. Seltzer, MD, Clinical Research Institute, San Diego; Frank F. Snyder, MD, Lovelace Scientific Resources, Albuquerque, NM; William Storms, MD, Asthma and Allergy Associates, PC, Colorado Springs, Colo; Mary Strek, MD, University of Chicago, Chicago, Ill; William Stricker, MD, Clinical Research of the Ozarks, Inc, Columbia, Mo; Richard J. Sveum, MD, Park Nicollet Clinic, Health System Minnesota, Minneapolis; David G. Tinkelman, MD, Atlanta Allergy and Immunology, Research Foundation, Riverdale, Ga; Alan A. Wanderer, MD, Clinical Research Group of Colorado, Englewood; James R. Taylor, MD, Pulmonary Consultants, Tacoma, Wash; Stephan Weisberg, MD, Allergy and Asthma Specialists, Minneapolis; Richard White, MD, University of California Davis Medical Center, General Internal Medicine Investigative Clinic, Sacramento, Calif; and James D. Wolfe, MD, Allergy and Asthma Associates, San Jose, Calif. ceptor antagonists, 17 possibly because of target cell receptor up-regulation. 18 Since receptor up-regulation is thought to occur within the first week of exposure, 19 it is unlikely that longer treatment durations with montelukast would result in rebound worsening of asthma. Studies with zafirlukast, another leukotriene receptor antagonist, and zileuton, a 5-lipoxygenase inhibitor, have demonstrated that these compounds also provide benefits in chronic asthma. Zafirlukast improved airway obstruction in a 6-week study, 6 and zileuton improved airway obstruction and patient-reported end points in a 12- week study. 2 These trials showed large variability in the treatment effects across end points, 6,7,2 in contrast to the consistent effect shown with montelukast in this trial. In this study, all end points were measured with high precision, leading to accurate and consistent treatment effect estimates. Spirometry data, transmitted via modem, were collected and assessed centrally, with timely feedback given to study centers. We believe that the standardized, centralized spirometry quality control instituted in this study was the reason not only for the accuracy of the spirometry measurements, but indirectly for the precision of all study end points. Further evidence of the benefit of centralized quality control was shown in the decreased variability (the root mean square error from the ANOVA model) of the data in this large clinical trial compared with that of a smaller dose-ranging study. 9 To our knowledge this is the first report of the use of an electronic, centralized spirometry control system in a therapeutic asthma clinical trial. The diary card measures (daytime asthma symptom scores, nocturnal awakening, -agonist use, and PEFR) demonstrated a near-maximal effect of montelukast within the first day of treatment, indicating a rapid therapeutic benefit. Such a rapid onset has not been seen with other leukotriene receptor antagonists or 5- lipoxygenase inhibitors used in the treatment of asthma. 7,21,22 Other controller agents for asthma, including cromolyn, nedocromil, and inhaled corticosteroids, also require a longer treatment duration before their effects become apparent. 23,24 Significant improvements in all quality-of-life domains (symptoms, activity, environment, and emotions) occurred with montelukast treatment. Previous work in this area 25 suggests that the magnitude of the treatment-related improvements observed in this study were clinically meaningful. The evaluation of quality of life is important because it determines the impact of therapy on the patient s daily life that is not captured by other end points. 14 Another important objective of chronic asthma therapy is the protection against episodes of worsening asthma. 26 Such episodes have been shown to contribute to morbidity and consume substantial asthma-related health resources. We found that montelukast protected significantly against asthma worsening. A 31% decrease in asthma exacerbation days and a 37% increase in asthma 1219 Downloaded From: on 1/8/218

8 control days were observed. In addition, montelukast provided protection against episodes of worsening asthma (need for oral corticosteroid rescue treatment or discontinuation from study therapy). These results confirmed findings from a previous montelukast trial 9 and were consistent with the improvements in the primary end points of this study. The effect of montelukast was generally consistent across patient prerandomization characteristics, including demographic variables and baseline values for the end points (FEV 1 and daytime symptom score), indicating that there was a similar clinical response to montelukast across subgroups of the asthmatic population studied. Montelukast provided clinical benefit in patients using concomitant inhaled corticosteroids, thus confirming previous clinical trials with montelukast. 8,27,28 It has been shown that oral corticosteroids do not inhibit the production of leukotrienes in the airways of asthmatic patients; this provides the biological basis for the additive effects of leukotriene receptor antagonists and corticosteroids. 29 It is currently believed that asthma is a syndrome of airway inflammation, characterized in part by increased numbers of blood eosinophils, which, with other inflammatory cells, infiltrate the airways. 3 Leukotrienes have been shown to enhance proliferation of bone marrow eosinophil and basophil precursors, 31 to attract eosinophils into the lung, 5 and to cause microvascular leakage. 5 The decrease in blood eosinophil counts over time, consistent with previous montelukast studies 9,28 and similar to that seen with inhaled corticosteroids, suggests that montelukast may have important effects on measures of asthmatic inflammation. A study with a 5- lipoxygenase inhibitor has shown similar results. 7 These observations suggest that the therapeutic effect of antileukotriene compounds may, in part, be caused by effects on inflammatory measures. In this study, montelukast was generally well tolerated. Clinical adverse events occurred with similar frequencies with montelukast and placebo treatments. Adverse events that occurred were generally transient and self-limited, and did not require discontinuation from study therapy. Laboratory adverse experiences were infrequent, mild, transient, and similar in frequency in the montelukast and placebo treatment groups. There were no differences in the occurrence of serum aminotransferase elevations between the montelukast and placebo groups, as have been reported with the 5-lipoxygenase inhibitor zileuton. 7 In conclusion, montelukast sodium, given orally at 1 mg once daily at bedtime during a 12-week treatment period, provided significant clinical benefit to patients with chronic asthma. It was generally well tolerated, with an adverse event profile comparable with that of placebo. Accepted for publication November 4, This study was supported by a grant from Merck Research Laboratories, Rahway, NJ. We thank Kerstin Malmstrom, PhD, for help in preparing the manuscript; Barbara Knorr, MD, for critical review of the manuscript; Elizabeth V. Hillyer, DVM, and Judy Evans for editorial assistance; and Jacquelyn McBurney and Gertrude Noonan for their excellent coordination of the study. Reprints: Theodore F. Reiss, MD, Merck Research Laboratories, RY , PO Box 2, Rahway, NJ 765. REFERENCES 1. 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