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Ioi70902.Pdf 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 mon- Results: Montelukast improved airway obstruction telukast sodium, a leukotriene receptor antagonist, in asth- (forced expiratory volume in 1 second, morning and matic patients aged 15 years or more. evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, “as-needed” Design: Randomized, multicenter, double-blind, placebo- b-agonist use, nocturnal awakenings) (P,.001 com- controlled, parallel-group study. A 2-week, single- pared with placebo). Montelukast provided near- blind, placebo run-in period was followed by a 12- maximal effect in these end points within the first day week, double-blind treatment period (montelukast of treatment. Tolerance and rebound worsening of asthma sodium, 10 mg, or matching placebo, once daily at bed- did not occur. Montelukast improved outcome end points, time) and a 3-week, double-blind, washout period. including asthma exacerbations, asthma control days (P,.001 compared with placebo), and decreased periph- Setting/Patients: Fifty clinical centers randomly allo- eral blood eosinophil counts (P,.001 compared with pla- cated 681 patients with chronic, stable asthma to receive pla- cebo). The incidence of adverse events and discontinu- cebo or montelukast after demonstrating a forced expira- ations from therapy were similar in the montelukast and tory volume in 1 second 50% to 85% of the predicted value, placebo groups. at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled b-agonist adminis- Conclusions: Montelukast, compared with placebo, sig- tration, a minimal predefined level of daytime asthma symp- nificantly improved asthma control during a 12-week toms, and inhaled b-agonist use. Twenty-three percent of treatment period. Montelukast was generally well toler- the patients used concomitant inhaled corticosteroids. ated, with an adverse event profile comparable with that of placebo. Primary End Points: Forced expiratory volume in 1 second and daytime asthma symptoms. Arch Intern Med. 1998;158:1213-1220 STHMA IS a significant matory cells, including eosinophils and mast worldwide health prob- cells, and are at least 1000 times more po- lem, accounting for $4.2 tent bronchoconstrictors than histamine or From the Departments of billion of health care costs methacholine in normal and asthmatic sub- Pulmonary/Immunology in the United States in jects.4 The leukotrienes mediate many of the (Drs Reiss and Seidenberg) 1995.1 Despite the development and in- pathophysiologicalprocessesassociatedwith and Biostatistics (Ms Shingo), A 2 Merck Research Laboratories, stitution of treatment guidelines, asthma asthma, including microvascular leakage, Rahway, NJ; NE Research remains a costly clinical problem, with a bronchoconstriction,andeosinophilrecruit- 5 Center, Inc, North Dartmouth, continuous need for new, innovative treat- ment into the airways. Agents that interrupt Mass (Dr Chervinsky); ments. Current therapies have limita- theactionoftheleukotrienes(5-lipoxygenase International Medical tions, including poor compliance (inhal- inhibitors and leukotriene receptor antago- Technology Consultants Inc, ers, dosage frequency) and side effects.3 nists) have demonstrated improvement of Prairie Village, Kan New, effective, well-tolerated oral thera- chronic asthma in clinical trials, thus pro- (Dr Dockhorn); and Allergy pies may have a substantial impact on the viding evidence for their role in asthma.6-9 and Asthma Center, Albany management of asthma. Montelukast sodium is a potent and Medical Center, Albany, NY The role of the cysteinyl leukotrienes specific leukotriene receptor antagonist10 (Dr Edwards). A list of the members of the Montelukast (leukotrienes C4,D4, and E4) in asthma has that has been shown to have substantial Clinical Research Study Group been clearly established. These leukotrienes blockade of airway leukotriene receptors 11 is given on page 1219. are produced and released from proinflam- 24 hours after oral dosing. This long du- ARCH INTERN MED/ VOL 158, JUNE 8, 1998 1213 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 PATIENTS AND METHODS at the prestudy visit. Patients who demonstrated compe- tence withthe use of these instruments and the ability to perform reproducible spirometry at each clinic visit were STUDY DESIGN eligible for period 2. This multicenter, randomized, double-blind, placebo- EXCLUSION CRITERIA controlled, 3-period, parallel-group trial compared the clini- cal effect of oral montelukast sodium, 10 mg once daily at Active upper respiratory tract infection within 3 weeks, acute bedtime, and placebo. The study consisted of a 2-week, sinusdiseaserequiringantibiotictreatmentwithin1week,emer- single-blind, placebo run-in period (period 1); a 12-week, gency department treatment for asthma within 1 month, or double-blind, active treatment period (period 2); and a 3- hospitalization for asthma within 3 months before the prestudy week, double-blind, placebo washout period (period 3). visit were study exclusions. Excluded medications included Clinic visits occurred every 2 weeks during period 1 and oral, inhaled (concomitant inhaled medication use was allowed every 3 weeks thereafter. for a subset of patients), and parenteral corticosteroids within The study was conducted at 50 study centers in the 1 month; cromolyn sodium, nedocromil sodium, terfenadine, United States between October 21, 1994, and August 13, and loratadine within 2 weeks; theophylline (oral and intra- 1995; 681 patients were randomly assigned, according to venous), b-agonists (oral or long-acting inhaled), and anticho- a computer-generated allocation schedule, to receive ei- linergic agents within 1 week; astemizole within 3 months; and ther a film-coated tablet of montelukast sodium, 10 mg, or immunotherapy initiated within 6 months before the prestudy matching placebo. In period 3, a subset of patients was visit. According to a standardized protocol, oral corticosteroids blindly switched from montelukast to placebo according were allowed for treatment of worsening asthma during pe- to the computer-generated allocation schedule. riods 2 and 3. Patients who required rescue during period 1, Written informed consent approved by the respec- more than 2 rescues during periods 2 and 3, or change in im- tive institutional review boards was obtained from each pa- munotherapy were discontinued from the study. tient. If the patient was younger than 18 years, consent was also obtained from the patient’s parent or guardian. EVALUATIONS INCLUSION CRITERIA The FEV1 and daytime asthma symptom score were pre- specified as primary end points. Other prespecified end Healthy, nonsmoking patients (male and female), aged 15 points were morning and evening peak expiratory flow rate years and older with at least 1 year of intermittent or per- (PEFR), daily use of inhaled short-acting as-needed b- sistent asthma symptoms, were enrolled. Female patients agonist, nights per week with nocturnal awakenings, asthma- had a negative serum b-human chorionic gonadotropin test specific quality of life, physician’s and patient’s global evalu- at the prestudy visit. All patients used short-acting in- ations, change in peripheral blood eosinophil counts, and haled b-agonists as needed to treat their asthma, and a per- asthma outcome end points including episodes of wors- centage of patients (not to exceed 25%) were allowed con- ening asthma (percentage of days with asthma exacerba- comitant inhaled corticosteroids at a constant dosage tions), use of rescue oral corticosteriods (percentage of pa- beginning at least 4 weeks before the prestudy visit. Pa- tients), discontinuation because of worsening asthma tients with non–life-threatening, clinically stable, concomi- (determined by whether additional asthma medications were tant diseases could be enrolled in the study. required), and asthma control days. Patients were eligible for randomization if they had, Spirometry was performed at each clinic visit between 6 on at least 2 of the 3 visits during period 1, a forced expi- and 9 AM, approximately 10 to 12 hours after the previous dose ratory flow in 1 second (FEV1) between 50% and 85% of of study medication and after b-agonist and short-acting an- the predicted value (after withholding b-agonist for at least tihistamines had been withheld for at least 6 and 48 hours, re- 6 hours) and an absolute increase in FEV1 of at least 15%, spectively.Patientsusinginhaledcorticosteroidswereinstructed 20 to 30 minutes after inhalation of b-agonist. In addi- to take the morning dose either an hour before or after a clinic tion, patients were required to have a minimum total 2- visit. The spirometry measurements were collected with a stan- week daytime asthma symptom score of 64 (a maximum dard spirometer (Nellcor/Puritan-Bennett PB 100/PB110, Len- score of 336 was possible) and to have used a daily aver- dena, Kan) and transmitted via modem to a central spirom- age of at least 1 puff of b-agonist during period 1. etry quality control center, where the data were reviewed to Patients received a peak flow meter (Mini-Wright;
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