Steven W. Yancey

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

BACKGROUND Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. Georges Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Oral Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma

BACKGROUND Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. METHODS In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment). Other outcomes included the rate of asthma exacerbations, asthma control, and safety. RESULTS The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P=0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P=0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P=0.04) and a reduction of 0.52 points with respect to asthma symptoms (P=0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms. (Funded by GlaxoSmithKline; SIRIUS ClinicalTrials.gov number, NCT01691508.).

A Comparison of Salmeterol with Albuterol in the Treatment of Mild-to-Moderate Asthma

BACKGROUND An effective, long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs. We compared a new long-acting, inhaled beta 2-adrenoceptor agonist, salmeterol, with a short-acting beta 2-agonist, albuterol, in the treatment of mild-to-moderate asthma. METHODS We randomly assigned 234 patients (150 male and 84 female patients 12 to 73 years old) to one of three treatment groups: one group received 42 micrograms of salmeterol twice daily, one received 180 micrograms of albuterol four times daily, and one received placebo. Treatment was assigned in a double-blind fashion, and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period. RESULTS Measurements of the forced expiratory volume in one second, performed hourly for 12 consecutive hours, showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart (6.3 vs. 4.9 liter.hr, P < 0.05). The difference was significant on day 1 and at week 4 of the study, but not at week 8 or 12. Salmeterol was also more effective than albuterol or placebo (with albuterol taken as needed) in increasing the morning peak expiratory flow rate: salmeterol induced a mean increase of 24 liters per minute over the pretreatment values, as compared with a decrease of 6 liters per minute with albuterol (P < 0.001) and an increase of 1 liter per minute with placebo (P = 0.002). The mean overall symptom score was improved most by salmeterol treatment (P < 0.05), with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent, respectively; there were no differences in results between albuterol treatment and placebo administration. We found no evidence of tolerance to the bronchodilating effects of salmeterol, and adverse reactions to all the treatments were infrequent and mild. CONCLUSIONS For the management of mild-to-moderate asthma, salmeterol given twice daily is superior to albuterol given either four times daily or as needed.

The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma

BACKGROUND Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate (FP) as the cornerstone of anti-inflammatory therapy for asthma. OBJECTIVE The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP as compared with increasing the dose of FP. METHODS In a multicenter, double-blind study conducted over 24-weeks, 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were randomly assigned to receive either salmeterol (42 microg twice daily) or FP 220 microg twice daily. The primary efficacy endpoint was morning peak expiratory flow. Secondary measures included FEV1, symptom scores, nighttime awakenings, and supplemental albuterol use. Safety was assessed by reported adverse events and asthma exacerbations. RESULTS The addition of salmeterol resulted in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP. Over weeks 1 to 24, morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily (P < .001) while the percent of symptom-free days increased from baseline by 26% of days as compared with 10% of days (P < .001). The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment. CONCLUSIONS The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinically and statistically superior to increasing the dose of FP.

Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma

BACKGROUND Salmeterol, a long-acting beta2 -agonist, and zafirlukast, a leukotriene receptor antagonist, are both indicated for the treatment of asthma in adolescent and adult patients. OBJECTIVE We sought to compare the effect of 4 weeks of treatment with inhaled salmeterol xinafoate versus oral zafirlukast in the treatment of persistent asthma. METHODS This was a randomized, double-blind, double-dummy, parallel-group, multicenter clinical trial. Patients, over 80% of whom were on a concurrent inhaled corticosteroid regimen, were treated for 4 weeks with either inhaled salmeterol xinafoate 42 microgram twice daily administered by means of a metered-dose inhaler or oral zafirlukast 20 mg twice daily. The primary efficacy measure was morning peak expiratory flow (PEF); secondary efficacy measures included evening PEF, asthma symptom scores, supplemental albuterol use, nighttime awakenings, sleep symptoms, asthma exacerbations, and FEV1. RESULTS Both inhaled salmeterol and oral zafirlukast resulted in within-group improvements from baseline in measures of pulmonary function, asthma symptoms, and supplemental albuterol use. Salmeterol treatment resulted in significantly greater improvements from baseline compared with zafirlukast for most efficacy measurements, including morning PEF (29.6 vs 13.0 L/min; P </= .001), percentage of symptom-free days (22.4% vs 8.8%; P </= .001), and percentage of days and nights with no supplemental albuterol use (30.5% vs 11.3%; P </= .001). There were no differences in safety profiles as assessed by adverse event monitoring. CONCLUSION In patients with persistent asthma, most of whom were concurrently using inhaled corticosteroids, treatment with inhaled salmeterol provided significantly greater improvement than oral zafirlukast in overall asthma control over the 4-week treatment period.

Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies

BACKGROUND Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds. METHODS We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab ( DREAM 75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per μL, ≥300 cells per μL, ≥400 cells per μL, and ≥500 cells per μL) and baseline blood eosinophil ranges (<150 cells per μL, ≥150 cells per μL to <300 cells per μL, ≥300 cells per μL to <500 cells per μL, and ≥500 cells per μL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis. FINDINGS Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL, predicted efficacy of mepolizumab was reduced. INTERPRETATION Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab. FUNDING GlaxoSmithKline.

Meta-analysis: Effects of Adding Salmeterol to Inhaled Corticosteroids on Serious Asthma-Related Events

Context Guidelines recommend adding long-acting -agonists to regimens of patients with asthma that is not controlled on inhaled corticosteroids alone. Is this safe? Contribution This meta-analysis summarizes 66 GlaxoSmithKline trials involving 20966 patients with persistent asthma. Trials compared twice-daily salmeterol, 50 g, plus inhaled corticosteroids with inhaled corticosteroids alone. Combination therapy did not appear to alter risk for asthma-related hospitalizations but did decrease risk for severe exacerbations requiring systemic corticosteroids. The only cases of asthma-related death and intubation occurred in patients receiving combination therapy. Caution Most trials were short and originally designed to assess lung function rather than clinical outcomes. The Editors Asthma is a chronic disease affecting nearly 20 million people in the United States and approximately 300 million people worldwide (1). In response to the growing burden of uncontrolled asthma, evidence-based guidelines were released in the early 1990s to bridge the gap between research and practice, with the objective of improving management. National and international asthma guidelines recommend that all patients with persistent asthma receive regular treatment with anti-inflammatory medication, preferably an inhaled corticosteroid. For patients whose asthma is not controlled by inhaled corticosteroids alone, guidelines recommend adding a long-acting -agonist (1, 2). Recently, concern about the role of long-acting -agonists in asthma management was raised in a randomized, observational study of more than 26000 patients (3). In this study, salmeterol compared with placebo added to usual therapy showed a small but statistically significant increase in severe asthma-related events, including asthma-related death. In contrast, the largest casecontrolled study to date of 532 asthma deaths (4) concluded that use of long-acting -agonists was not associated with increased risk for asthma-related death compared with other therapies. The Cochrane Airways Group has published several meta-analyses of clinical trials that studied the combination of inhaled corticosteroids and long-acting 2-agonists and concluded that exacerbations of asthma were infrequent and occurred at similar or lower rates in participants receiving concurrent long-acting -agonists and inhaled corticosteroids than in those receiving inhaled corticosteroids alone (57). Salpeter and colleagues (8) performed a meta-analysis examining life-threatening or fatal asthma exacerbations in participants using long-acting -agonists. Approximately 50% of the participants did not receive concurrent inhaled corticosteroid therapy, and the results showed that, although rare, asthma-related hospitalization and death occurred more frequently in participants receiving long-acting -agonists than in those receiving placebo. Because asthma guidelines clearly state that long-acting -agonists should be taken concurrently with inhaled corticosteroids (1, 2), we conducted a meta-analysis of published and unpublished GlaxoSmithKline trials that evaluated use of salmeterol and inhaled corticosteroids compared with inhaled corticosteroid monotherapy alone. Methods Data Sources and Searches We reviewed all studies posted as of September 2007 to the GlaxoSmithKline Clinical Trials Registry (ctr.gsk.co.uk/welcome.asp) for the following GlaxoSmithKline drugs: fluticasone propionate/salmeterol (Advair), salmeterol xinafoate (Serevent), and fluticasone propionate (Flovent). This registry is a repository of data from GlaxoSmithKline-sponsored clinical trials. We also searched MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews from 1982 to September 2007. These searches were not restricted to studies published in English. Terms included salmeterol, -agonist, long-acting -agonist, inhaled corticosteroids, fluticasone propionate, budesonide, triamcinolone acetonide, beclomethasone dipropionate, randomized, controlled clinical trial, asthma, Advair, and Seretide. Finally, we supplemented these searches by reviewing references from published reviews. Study Selection Three reviewers perused the GlaxoSmithKline registry and search outputs (titles and abstracts) to identify randomized, controlled trials that compared the use of inhaled corticosteroids plus salmeterol with inhaled corticosteroids alone in patients with asthma. We selected randomized, double-blind, parallel-design, long-term dosing studies (range, 1 to 52 weeks) that used the approved dosage of salmeterol (50 g twice daily) in the United States and had been completed and analyzed by 30 September 2007. We did not exclude any trials on the basis of language. We excluded uncontrolled, open-label studies; single-dose studies; and crossover studies. Data Extraction and Quality Assessment One reviewer extracted information about participants, interventions, and comparisons from trials in the GlaxoSmithKline database, registry, or publications, and a second reviewer doubled-checked this information. One reviewer extracted information about trials that were not sponsored by GlaxoSmithKline. We did not use a specific checklist or scale to assess the quality of the trials: Protocols for the GlaxoSmithKline trials met the International Conference on Harmonisation guidelines. For these trials, a participant could spontaneously report adverse events. Study personnel solicited these participants by regular interviews and asked standardized, open-ended questions about any changes in their health status. The interval for these interviews was defined by the individual protocols but generally did not exceed 4 weeks. All GlaxoSmithKline trials report case narratives of serious adverse events, which include hospitalization, intubation, or death. We sent case narratives of reported serious adverse events that occurred during the randomized, double-blind phase of the GlaxoSmithKline trials to 3 physicians. These physicians, who were blinded to drug assignment in each case, independently reviewed the narratives and adjudicated the asthma relationship for hospitalization, intubation, and death status of each case. Any disagreements about adjudications were resolved through consensus of the 3 physicians. Statistical Analysis We used 2 methods to pool GlaxoSmithKline data on asthma-related hospitalizations and severe asthma-related exacerbations that required systemic corticosteroids. First, we calculated risk differences by using data from GlaxoSmithKline trials that met inclusion criteria (even those without events). We applied a treatment group continuity correction for trials in which at least 1 of the treatment groups had no events. In sensitivity analyses, we used 0.01, 0.001, and 0.0001 continuity corrections (9). Second, we used the Peto odds ratio method, which excludes trials with no events and performs reasonably well when imbalance in trial group size is low, the rate of events is low (1%), and the effect size is small (10, 11). For all estimates, we calculated 95% CIs (12, 13). We used the Cochran Q test and I 2 to evaluate statistical heterogeneity. All analyses were based on fixed-effects models and were conducted with StatsDirect statistical software, version 2.6.6 (Sale, United Kingdom) (14). Role of the Funding Source GlaxoSmithKline sponsored most trials summarized in this review. GlaxoSmithKline also supported data collection, analyses, manuscript preparation, and data interpretation for the review. All authors approved the manuscript for submission. Results Of 1218 reports identified in the combined searches, we found 80 randomized trials that compared salmeterol plus inhaled corticosteroids with inhaled corticosteroids alone (Figure 1). Of these, we excluded 4 short crossover trials that involved a total of 72 participants and 3 open-label trials that included 452 participants. None of the 7 excluded trials reported any asthma-related deaths, intubations, or hospitalizations. One trial (SLGT26) included in the current analysis had 3 groups. We excluded the group that involved 244 participants who were assigned to a dose of salmeterol (100 g twice daily) that exceeded the current recommendation. There were 3 asthma-related hospitalizations but no deaths in this excluded treatment group. Figure 1. Study flow diagram. GSK = GlaxoSmithKline. *Studies could contribute to more than 1 subanalysis. Trial Characteristics Seven trials that were not sponsored by GlaxoSmithKline met eligibility criteria. These trials involved a total of 503 participants (1521). None reported hospitalization, intubation, or death in a participant receiving salmeterol plus inhaled corticosteroids or inhaled corticosteroids alone. Because we did not have access to individual case narratives of adverse events in these trials, we did not include them in the quantitative analyses. The GlaxoSmithKline registry included 66 eligible trials that involved a total of 20966 participants (Appendix Table 1). In these trials, 10400 participants received inhaled corticosteroids plus salmeterol and 10566 received inhaled corticosteroids alone. The median trial duration was 12 weeks (range, 1 to 52 weeks). Sample sizes ranged from 12 to 3416. The mean age of participants was about 38 years. Forty-four percent were men, and 82% were white. Most had moderate to severe persistent asthma. The overall rate of withdrawal for any reason was about 14% among participants receiving inhaled corticosteroids plus salmeterol and about 17% among those receiving inhaled corticosteroids alone. Appendix Table 1. Included Studies Most trials used a lung function measure (FEV1 or peak expiratory flow) as the primary end point. In a few studies, the primary end point was a measure of asthma control, such as exacerbations or symptoms. The largest study (SAM40027) used a composite measure of asthma control that integrated lung function measures as well as symptom control and exacerbations as the primary e

β2-Receptor Polymorphisms in Patients Receiving Salmeterol with or without Fluticasone Propionate

RATIONALE Retrospective pharmacogenetic studies have questioned whether patients with asthma who are arginine homozygous at the beta(2-)adrenergic receptor (position 16) should use long-acting beta-agonists. OBJECTIVES To examine whether the response to salmeterol alone or in combination with an inhaled corticosteroid is influenced by beta- receptor polymorphisms. METHODS Subjects using only as-needed albuterol were screened and completed two sequential open-label run-in periods (8 wk on as-needed albuterol; 8 wk on as-needed ipratropium). Five hundred forty-four subjects were randomized by Arg16Gly genotype to salmeterol alone or with fluticasone propionate for 16 weeks. Change from baseline in morning peak expiratory flow was the primary endpoint. MEASUREMENTS AND MAIN RESULTS Lung function responses were sustained over treatment and no statistically significant changes from baseline between genotypes within treatments were observed. Overall mean changes in morning peak flow for salmeterol with fluticasone propionate were 32.6 L/min (Arg/Arg vs. Gly/Gly, 95% confidence interval [CI], -6.3, 22.1), 25.9 L/min (Arg/Arg vs. Arg/Gly, 95% CI, -7.1, 21.3), and 24.9 L/min (Arg/Gly vs. Gly/Gly, 95% CI, -13.0, 14.6), and for salmeterol alone were 19.4 L/min (Arg/Arg vs. Gly/Gly, 95% CI, -1.7, 21.4), 24.6 L/min (Arg/Arg vs. Arg/Gly, 95% CI, -13.0, 10.6), and 12.4 L/min (Arg/Gly vs. Gly/Gly, 95% CI, -0.2, 22.3) for Arg/Arg, Arg/Gly, and Gly/Gly genotypes, respectively. Other measures of asthma control showed similar responses. CONCLUSIONS The results showed no evidence of a pharmacogenetic effect of beta-receptor variation on salmeterol response. Clinical trial registered with www.clinicaltrials.gov (NCT 00102882).

Blood Eosinophil Count Is a Useful Biomarker to Identify Patients with Severe Eosinophilic Asthma

RATIONALE Measurement of sputum or blood eosinophils may allow identification of a severe eosinophilic asthma population responsive to mepolizumab. OBJECTIVES The primary objective was assessment of a single blood eosinophil measurement to predict future eosinophil measurements in the following year versus using multiple blood eosinophil measurements. In addition, we examined whether a single sputum or blood eosinophil measurement was a useful biomarker for predicting treatment response to mepolizumab. METHODS Based on data from placebo subjects (n = 155), we determined whether a blood eosinophil count of 150/μl or greater at screening remained on average above this level during the following year. The rate of exacerbation reduction in the sputum substudy population based on the screening blood eosinophil count and sputum eosinophils was evaluated. MEASUREMENTS AND MAIN RESULTS Of 115 patients with eosinophils 150/μl or greater at screening, 98 (85%) remained above this level in their post-screening average. Using the average of two, three or four measurements 150/μl or greater, 97 (85%), 103 (90%), and 105 (92%) have postscreening averages above 150/μl. Mepolizumab reduced exacerbations by 69% (95% confidence interval [CI] = 41-83%) in subjects with baseline sputum eosinophils of 3% or greater compared with 66% (95% CI = 7-87%) in subjects with baseline sputum eosinophils under 3%. The reduction was 72% (95% CI = 41-83%) in subjects with blood eosinophils of 150/μl or greater compared with 30% (95% CI = -134 to 79%) in subjects with blood eosinophils under 150/μl. CONCLUSIONS A single measurement of 150/μl or greater predicted the average of subsequent measurements being 150/μl or greater in 85% of this population. Using an average of multiple measurements only marginally increases the sensitivity. Sputum eosinophils did not predict treatment response with mepolizumab.

Fluticasone Propionate Nasal Spray Is Superior to Montelukast for Allergic Rhinitis While Neither Affects Overall Asthma Control

BACKGROUND Asthma and allergic rhinitis are both highly prevalent diseases and often coexist in patients. OBJECTIVE To investigate the effect of rhinitis therapy on asthma outcomes in adult and adolescent patients with both seasonal allergic rhinitis (SAR) and persistent asthma. METHODS A total of 863 patients (mean baseline FEV1 81% predicted) were randomized to receive open-label fluticasone propionate/salmeterol (FSC), 100/50 microg bid for 4 weeks, plus either blinded fluticasone propionate aqueous nasal spray (FPANS) 200 microg/d, montelukast 10 mg/d, or placebo. Patients kept daily records of peak expiratory flow (PEF), asthma, and rhinitis symptoms and rescue albuterol use. RESULTS FPANS added to FSC resulted in superior outcomes for daytime total nasal symptom scores (D-TNSS) and individual daytime nasal specific symptoms (congestion, rhinorrhea, sneezing, and itching) compared with montelukast plus FSC and placebo plus FSC (p < or = 0.001). Montelukast plus FSC was superior to placebo plus FSC only for D-TNSS and itching and sneezing. Morning PEF, asthma symptoms, and rescue albuterol use improved significantly (p < or = 0.001) in all treatment groups, but improvements were comparable across the treatment groups. CONCLUSION In patients with persistent asthma treated with FSC, the addition of montelukast or FPANS for the treatment of SAR resulted in no additional improvements in overall asthma control compared with FSC alone. However, FPANS provided superior rhinitis control compared with montelukast. These data suggest that asthma and rhinitis should each be optimally treated.