Edwin A. Bronsky

Oral Montelukast Compared with Inhaled Salmeterol To Prevent Exercise-Induced Bronchoconstriction: A Randomized, Double-Blind Trial

Exercise-induced bronchoconstriction is common in patients with chronic asthma (1). Airway cooling or desiccation during exercise may trigger activation of mast cells and release of such mediators as histamine and cysteinyl leukotrienes, resulting in bronchospasm (1, 2). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4), synthesized from arachidonic acid through the 5-lipoxygenase pathway, are potent bronchoconstrictors, with an effect greater than 1000 times that of histamine (3-5). Several researchers have demonstrated an increase in urinary concentrations of LTE4 after exercise (6, 7). Prophylaxis against exercise-induced bronchoconstriction with inhaled mast cell-stabilizing agents and short-acting -agonists must be administered 15 to 30 minutes before exercise. The long-acting inhaled -agonist salmeterol protects against exercise-induced bronchoconstriction for up to 12 hours, thus providing more flexibility in the dosing schedule for active patients with asthma (8, 9). However, in some patients, tolerance to salmeterol develops with long-term use, and the level of bronchoprotection diminishes by 6 to 9 hours (10-12). Montelukast sodium, a leukotriene receptor antagonist, is a potent oral medication for the treatment of asthma. The leukotriene receptor antagonists have demonstrated a significant bronchoprotective effect with exercise after one or two doses (13, 14). In patients with exercise-induced bronchoconstriction, short-term treatment with montelukast (Singulair, Merck & Co., Inc., Whitehouse Station, New Jersey) given once daily diminished the postexercise response, as described by the area under the FEV1 time curve (AUC0-60 min), by more than 50%, even at the end of the dosing interval (20 to 24 hours after administration) (15, 16). Furthermore, tolerance to the bronchoprotective effects of montelukast did not occur with long-term administration (17). We sought to test the hypothesis that the bronchoprotective effects of montelukast were greater than those of salmeterol in patients with chronic asthma who experienced exercise-induced bronchoconstriction. Methods Design We conducted a randomized, parallel-group study consisting of a 2-week, single-blind placebo baseline period followed by an 8-week, double-blind treatment period with montelukast sodium (10-mg tablet taken orally once in the evening) or inhaled salmeterol (50-g aerosol formulation [2 puffs] taken twice daily). Seventeen clinical study sites participated in the trial. To mask formulation differences, a double-dummy treatment regimen was used. Each patient received one tablet daily (active agent or matching placebo) or one inhaler twice daily (active agent or matching placebo) for both the single-blind and double-blind treatment periods. A computer-generated allocation schedule with a blocking factor of 4 was produced by the statistician. Each center was given a block of allocation numbers that were assigned sequentially to consecutive randomly assigned patients. Spirometric measurements were obtained before and after standardized exercise challenges at the beginning and end of the baseline period, within the first 3 days of the double-blind treatment period, and at weeks 4 and 8 of the treatment period. Additional measurements were physical examination, vital signs, electrocardiography, chest radiography, and laboratory tests (hematology, chemistry profile, and urinalysis). At each visit, all spontaneously reported adverse events were recorded. The protocol was approved by the institutional review board of each site, and written informed consent was obtained from each patient. Inclusion Criteria Male and female patients 15 to 45 years of age with a history of chronic asthma were enrolled. All patients had an FEV1 of at least 65% of the predicted value at rest and a decrease in FEV1 of at least 20% after a standardized exercise challenge on two occasions during the baseline period. All patients had been nonsmokers for at least 1 year and had a smoking history of less than 15 pack-years. Exclusion Criteria Persons who had upper respiratory infection or exacerbation of asthma requiring emergency care within the past month or were hospitalized for asthma in the past 3 months were excluded. Use of oral or inhaled corticosteroids, theophylline, cromolyn sodium, nedocromil, oral -agonist, and long-acting antihistamines was prohibited before and during the study. Use of inhaled albuterol for symptomatic relief of asthma and use of short-acting antihistamines were permitted. Evaluations A standard spirometer (Puritan-Bennett PB100/PB110, Puritan-Bennett, Wilmington, Massachusetts) was used to obtain all spirometric measurements according to American Thoracic Society standard criteria (18). Patients had to have discontinued use of inhaled short-acting -agonists for 6 hours before the visit. Exercise testing was done in the early afternoon near the trough of effect for both drugs according to a method described elsewhere (17). Measurements were obtained 20 and 5 minutes before exercise (prechallenge period). Exercise challenge was performed only if the average FEV1 in the prechallenge period was greater than 65% of predicted; otherwise, the test was rescheduled. Patients exercised on a treadmill while inhaling room temperature, compressed, dry air. During the first test, the speed and gradient of the treadmill were adjusted to achieve 80% to 90% of the patients age-predicted maximum heart rate. The settings were maintained for a total of 6 minutes; the same settings were used for future tests. This level of exercise has been used to quantify the level of bronchoconstriction associated with regular exercise (19). Serial spirometric measurements were obtained at 0, 5, 10, 15, 30, 45, and 60 minutes after exercise (postexercise period). Additional measurements were carried out at 15-minute intervals for up to 90 minutes if the patients FEV1 had not returned to within 5% of the prechallenge value by 60 minutes. If the patients FEV1 did not return to the prechallenge value by 90 minutes after exercise, a rescue dose of inhaled -agonist was administered at the discretion of the study investigator. Statistical Analysis An all-patients-treated analysis, which included patients with a baseline visit and at least one post-randomization visit, was performed. The change from baseline in the maximal percentage decrease in FEV1 after exercise at the end of 8 weeks of treatment was the primary end point. Analysis of variance was used to compare the two treatment groups. The analysis of variance model included terms for treatment, center, and the interaction of treatment and center. Ninety-five percent CIs for within-group means and the difference between groups were constructed to assess the magnitude of the treatment effect. Analysis of variance on the ranked data was used to analyze percentage inhibition for all end points. In the event of early termination of the exercise challenge because of administration of rescue medication, the largest percentage decrease in FEV1 achieved before administration of rescue medication was used in the analysis. Secondary end points were change from baseline for maximal percentage decrease in FEV1 at days 1 to 3 and week 4, the time required after maximal decrease in FEV1 to return within 5% of prechallenge values (time to recovery), and the AUC0-60 min at all visits. The mean of the 20- and 5-minute prechallenge measurements was used as the pre-exercise FEV1 value. If a patient required rescue with inhaled -agonist during the postexercise period, the last recorded FEV1 value was used and carried forward for all subsequent readings and 100 minutes was entered for the end point of time to recovery. The AUC0-60 min was calculated by using the trapezoidal method. If a patients FEV1 did not decrease below 95% of the prechallenge value, the time to recovery was assigned a value of zero. The persistence of effect over time was assessed by using a repeated-measures fixed-effects model with terms for center, treatment group, time, and the interaction of treatment group and time to calculate the rate of change over the treatment period. Persistence of effect was defined as a slope of zero. The magnitude of the slopes for each treatment group was estimated, and 95% CIs were calculated. An overall test of equal slopes between the treatment groups was examined, and a 95% CI on the difference in slopes between treatment groups was provided. The number and percentage of patients requiring rescue medication during or at the end of the exercise test were summarized by treatment group at each time point. In addition, the number and percentage of patients whose decrease in FEV1 from pre-exercise levels was less than 10%, 10% to 20%, 20% to 40%, and greater than 40% were summarized by treatment group for each visit. The overall incidence of adverse events and laboratory abnormalities was assessed by using the Fisher exact test, and within-group changes in the number of laboratory abnormalities were assessed by using the McNemar test. Descriptive statistics were provided by treatment group for patient demographic characteristics, clinical characteristics, and baseline profile. The study was designed with a sample size of 160 patients (80 patients per treatment group) to have 95% power (two-sided test at =0.05) to detect a 7% difference in the mean change in maximal percentage decrease in FEV1 between treatments. All statistical analyses were performed by using SAS software, version 6 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source Funding for this trial was provided by Merck & Co., Inc., Whitehouse Station, New Jersey. Personnel from Merck U.S. Human Health, Clinical Development department played a significant role in the design, conduct, and analysis of the trial. The trial was conducted in accordance with guidelines for clinical trials of investigational agents established by U.S. regulatory authorities. Results Pati

Growth in asthmatic children treated with fluticasone propionate

OBJECTIVE To determine whether inhaled fluticasone propionate has long-term effects on growth in children with persistent asthma. STUDY DESIGN In a double-blind, randomized, parallel-group, multicenter study, 325 prepubescent children with persistent asthma and normal growth rates were treated with placebo or inhaled fluticasone propionate powder 50 microg or 100 microg administered twice daily by a breath-actuated device for 1 year. Growth was evaluated monthly, whereas other safety variables and pulmonary function were evaluated periodically. RESULTS The prepubescent patients showed no statistically significant differences in mean height, mean growth velocity, or mean skeletal age between any of the treatment groups at any time. Over a period of 1 year, mean height (+/- SE) increased 6.15 +/- 0.17 cm in the placebo group, 5.94 +/- 0.16 cm in the fluticasone propionate 50 microg group, and 5.73 +/- 0.13 cm in the fluticasone propionate 100 microg group (p = 0.308, overall). CONCLUSIONS Prepubescent children treated with fluticasone propionate 50 microg and 100 microg administered twice daily for 1 year grew at rates similar to placebo-treated control subjects and at rates equal to expected growth velocity for age.

Fluticasone propionate aerosol for the treatment of adults with mild to moderate asthma

BACKGROUND Recent emphasis on the control of airway inflammation in asthma highlights the need for safe and effective antiinflammatory agents. Fluticasone propionate is one of the most potent antiinflammatory corticosteroids developed to date. OBJECTIVE This study assessed the safety and efficacy of fluticasone propionate aerosol in the treatment of mild to moderate asthma. METHODS Fluticasone propionate aerosol (25, 100, or 500 micrograms twice daily) or placebo was given for as long as 8 weeks to adults with mild to moderate asthma in a randomized, double-blind, parallel-group study. Patients were removed from the study if they showed predefined signs of worsening asthma. RESULTS Sixty-three percent of placebo-treated patients and 23%, 13%, and 4% of patients treated with fluticasone propionate 25, 100, and 500 micrograms twice daily, respectively, were removed from the study. Mean forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow at midexpiratory phase at weekly visits throughout the study demonstrated that fluticasone propionate was more efficacious than placebo in maintaining asthma control. Measurements of peak expiratory flow and symptom scores significantly improved and nighttime awakenings and albuterol use to treat symptoms significantly declined in fluticasone propionate-treated groups relative to the placebo-treated group. Differences among fluticasone propionate groups for these variables were not statistically significant. Incidence and severity of adverse events were similar across groups. Fluticasone propionate did not affect morning or stimulated plasma cortisol concentrations, although slight, transient reductions in urinary free cortisol and urinary 17-hydroxy steroids occurred in the group receiving 500 micrograms fluticasone propionate twice daily. CONCLUSION These data indicate that fluticasone propionate provides safe and effective treatment for mild to moderate asthma.

Dose-related efficacy of budesonide administered via a dry powder inhaler in the treatment of children with moderate to severe persistent asthma.

OBJECTIVE To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler (Turbuhaler) in children with moderate to severe persistent asthma. STUDY DESIGN In our randomized, double-blind, placebo-controlled, parallel-group, multicenter study, a total of 404 children with asthma, who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy, were randomly assigned to receive either 100, 200, or 400 micrograms of budesonide or placebo twice daily for 12 weeks. At baseline, mean forced expiratory volume in 1 second (FEV1) was 74.6% (range, 30.7% to 123.3%) of the predicted normal value. RESULTS Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function (morning peak expiratory flow and FEV1), in asthma symptoms, and with a significant decrease in inhaled beta 2-agonist use in comparison with placebo. Improvements were evident within 2 weeks and were maintained throughout the 12 weeks. Budesonide treatment had no significant effect on hypothalamic-pituitary-adrenal axis function, and the incidence of reported adverse events was similar in all treatment groups. CONCLUSION Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children (6 to 18 years of age) with moderate to severe persistent asthma.

A dose-ranging study of fluticasone propionate aqueous nasal spray for seasonal allergic rhinitis assessed by symptoms, rhinomanometry, and nasal cytology

Fluticasone propionate is a new glucocorticosteroid with potent topical activity. In a double-blind, randomized, parallel-group study, 423 adult patients with moderate to severe seasonal allergic rhinitis received placebo or fluticasone propionate aqueous nasal spray at doses of 25, 100, or 400 micrograms twice daily (b.i.d.) for 2 weeks. Efficacy was evaluated by nasal symptom scores, nasal airflow, nasal cytology, and global evaluation. All doses of fluticasone propionate were significantly better than placebo in reducing symptoms of seasonal allergic rhinitis. Patients receiving the largest dose of fluticasone propionate (400 micrograms b.i.d.) had a slightly greater reduction (not significant) in symptom scores than patients receiving the smallest dose (25 micrograms b.i.d.). Symptom improvement was evident within 3 days of treatment. Nasal airflow improved in the groups treated with fluticasone propionate, 100 and 400 micrograms b.i.d. Examination of nasal cytograms revealed a striking decrease in both eosinophils and basophils in all three groups receiving active treatment compared with placebo. There were few adverse events and no treatment-related abnormalities in laboratory assays or evaluations of hypothalamo-pituitary-adrenocortical axis function. Comparison of treatment groups indicated that fluticasone propionate aqueous nasal spray was as safe as placebo at the doses studied.

The leukotriene D4-receptor antagonist zafirlukast attenuates exercise-induced bronchoconstriction in children.

OBJECTIVE To determine the effects of zafirlukast on exercise-induced bronchoconstriction in children. STUDY DESIGN Exercise challenges were done 4 hours after single oral doses of zafirlukast or placebo were administered in asthmatic children (6 to 14 years) treated with beta 2-agonists alone. Subjects randomized to treatment had a >/=20% decrease in forced expiratory volume in 1 second (FEV1 ) after a screening challenge. In a randomized, double-blind, 3-way, crossover design, group 1 (n = 20) received placebo and 5 and 20 mg zafirlukast, and group 2 (n = 19) received placebo and 10 and 40 mg zafirlukast. Maximal percentage fall in FEV1, area under the curve, and time to recovery of FEV1 to within 5% of baseline after the challenge were compared with analysis of variance. RESULTS Mean values for maximal fall in FEV1 ranged from -8.7% +/- 1.7% to -11.1% +/- 1.9% after zafirlukast compared with -17.1% +/- 1.8% and -16.3% +/- 1.9% after placebo. Differences from placebo for fall in FEV1 and area under the curve were significant (P </=.05) after 5, 20, and 40 mg zafirlukast and approached significance (P </=.08) after 10 mg zafirlukast. After all zafirlukast doses, recovery times (means of 5 to 7 minutes) decreased significantly (P </=.05) and by approximately half compared with placebo (11 and 14 minutes). Safety assessments did not differ among treatments. CONCLUSION Four hours after dosing, zafirlukast attenuated exercise-induced bronchoconstriction in children.

Results of the First U.S. Double-Blind, Placebo-Controlled, Multicenter Clinical Study in Asthma with Pranlukast, a Novel Leukotriene Receptor Antagonist

Pranlukast (SB 205312; ONO-1078), a potent, orally active selective cysteinyl-leukotriene receptor antagonist (LTRA), was developed in Japan for the treatment of asthma. This article reports results of the initial U.S. clinical evaluation of pranlukast. The primary objective of this multicenter study was to evaluate the safety and tolerability of pranlukast administered at doses of 337.5 mg b.i.d. and 450 mg b.i.d. in 65 patients with mild to moderate asthma. Pranlukast, a novel LTRA, is safe and well tolerated at doses of 337.5 mg b.i.d. and 450 mg b.i.d. Pranlukast has demonstrated clinical activity in patients with asthma.

Once daily fluticasone propionate is as effective for perennial allergic rhinitis as twice daily beclomethasone diproprionate

BACKGROUND Fluticasone propionate aqueous nasal spray, a new potent corticosteroid, is effective when given once or twice daily for seasonal allergic rhinitis. METHODS Fluticasone propionate was compared with beclomethasone dipropionate in a multicenter double-blind, randomized, placebo-controlled, parallel-group study in 466 patients with perennial allergic rhinitis. Adults and adolescents (aged 12 to 71 years) with moderate to severe symptoms, nasal eosinophilia, and a positive skin test reaction (> or = 2+) to a perennial allergen received fluticasone propionate aqueous nasal spray 100 micrograms twice daily or 200 micrograms once daily, or beclomethasone dipropionate aqueous nasal spray 168 micrograms twice daily, or placebo for 6 months. RESULTS Clinician- and patient-rated scores for nasal obstruction (including obstruction on awakening), rhinorrhea, sneezing, and nasal itching were reduced by the first visit at 7 days after initiation of active treatment and remained lower than those of patients receiving placebo throughout the 6-month treatment period. Nasal eosinophilia was reduced in significantly more patients receiving active treatment. The incidence of adverse events was similar in all four treatment groups except for blood in nasal mucus, which was reported by significantly more patients in the two twice-daily active treatment groups compared with the placebo group. There was no evidence of systemic effects of fluticasone propionate. There were no significant differences between fluticasone propionate given once or twice daily or beclomethasone dipropionate given twice daily for any efficacy or safety evaluation. CONCLUSIONS Fluticasone propionate aqueous nasal spray given once daily in the morning is safe and effective therapy for perennial allergic rhinitis and is as effective as twice daily dosing with fluticasone propionate or beclomethasone dipropionate.

A dose-ranging study of mometasone furoate aqueous nasal spray in children with seasonal allergic rhinitis

BACKGROUND The efficacy and safety of mometasone furoate aqueous nasal spray (MFNS; Nasonex) 200 microg once daily for the treatment and prophylaxis of seasonal allergic rhinitis (SAR) and treatment of perennial rhinitis have been demonstrated in adults. However, the dose response of MFNS in pediatric patients has not yet been characterized. OBJECTIVE This study was conducted to determine the dose-response relationship of 3 different doses of MFNS in a pediatric population. METHODS This was a multicenter, double-blind, active- and placebo-controlled study of 679 children 6 to 11 years of age with histories of SAR and documented positive skin test responses. Patients were randomized to one of the following treatment groups for 4 weeks: MFNS 25 microgram once daily, MFNS 100 microgram once daily, MFNS 200 microgram once daily, beclomethasone dipropionate 84 microgram twice daily (168 microgram/day), or placebo. Physician evaluations were performed at days 4, 8, 15, and 29, and patient evaluations were analyzed for days 1 to 15 and 16 to 29. RESULTS The mean reduction from baseline in physician-evaluated total nasal symptom scores at day 8 (the primary efficacy variable) was significantly greater in the MFNS and beclomethasone dipropionate groups than in the placebo group (P </=.02). No significant differences were observed among the 3 MFNS groups. However, as treatment continued, symptoms in patients treated with MFNS 100 or 200 microgram once daily continued to improve, whereas those treated with MFNS 25 microgram once daily demonstrated little further improvement. By day 29, MFNS 100 and 200 microgram once daily both were significantly more effective than MFNS 25 microgram once daily in relieving symptoms of SAR, but MFNS 200 microgram provided no additional benefit over MFNS 100 microgram. All doses of MFNS were well tolerated, and cosyntropin stimulation tests performed before and after treatment found no evidence of hypothalamic-pituitary-adrenal axis suppression. CONCLUSION These results indicate that the most appropriate therapeutic dosage of MFNS in the treatment of SAR in children 6 to 11 years of age is 100 microgram once daily. In addition, MFNS at doses up to 200 microgram once daily for 4 weeks was well tolerated and had no detectable effects on hypothalamic-pituitary-adrenal axis function.

Effectiveness and Safety of Fexofenadine, a New Nonsedating H1-Receptor Antagonist, in the Treatment of Fall Allergies

Fexofenadine HCl is a new, nonsedating H1-receptor antagonist approved for treatment of seasonal allergic rhinitis (SAR). In a double-blind, randomized, placebo-controlled, multicenter trial, 588 patients with fall SAR rated the severity of their symptoms using a scoring system at a screening visit and during a 3-day placebo lead-in period. Patients who did not respond to placebo and met symptom severity criteria were randomized to receive placebo or fexofenadine HCl at 40, 60, or 120 mg bid at 7:00 a.m. and 7:00 p.m. for 14 days. Patients continued to rate the severity of their symptoms immediately before receiving each dose (at trough). A total of 545 patients were included in an intent-to-treat analysis. The change from baseline in the primary efficacy variable (average daily 7:00 p.m. reflective symptom scores) was significantly greater in patients receiving all dosages of fexofenadine HCl than placebo (p < 0.01). All active dosages produced significant decreases (p < 0.05) in secondary end points: 7:00 a.m. reflective symptom scoring; 7:00 a.m. and 7:00 p.m. scoring 1-hour before dose; and bedtime scoring 1-3 hours after the 7:00 p.m. dose. All dosages of fexofenadine HCl were well tolerated, and no effect on QTc was observed. In conclusion, fexofenadine HCl is safe and effective in the treatment of fall SAR, with 60 mg bid being the optimal therapeutic dosage.