Hector Ortega

Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial

BACKGROUND Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. METHODS We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. FINDINGS 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. INTERPRETATION Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. FUNDING GlaxoSmithKline.

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.).

An Antibody Against IL-5 Reduces Numbers of Esophageal Intraepithelial Eosinophils in Children With Eosinophilic Esophagitis

BACKGROUND & AIMS The role of interleukin (IL)-5 in the pathogenesis of eosinophilic esophagitis (EoE) has been established in animal models; anti-IL-5 therapy has been reported to be effective in adults. We investigated whether IL-5 has a role in accumulation of esophageal eosinophils in children with EoE and whether therapy with mepolizumab, an antibody against IL-5, reduces the number of esophageal intraepithelial eosinophils in children with EoE. METHODS We performed an international, multicenter, double-blind, randomized, prospective study of 59 children with EoE, defined as baseline peak count of esophageal intraepithelial eosinophils of ≥ 20 in at least 1 high-power field (hpf). Patients received an infusion every 4 weeks (a total of 3 infusions) of 0.55, 2.5, or 10 mg/kg mepolizumab. No placebo group was used. RESULTS Baseline peak and mean esophageal intraepithelial eosinophil counts were (mean ± SE) 122.5 ± 8.78 and 39.1 ± 3.63 per hpf, respectively. Four weeks after the third infusion, peak eosinophil counts were <5 per hpf in 5 of 57 children (8.8%); we did not observe differences among groups given different doses of mepolizumab. Reduced peak and mean eosinophil counts, to <20 per hpf, were observed in 18 of 57 (31.6%) and 51 of 57 (89.5%) children, respectively. Peak and mean esophageal intraepithelial eosinophil counts decreased significantly to 40.2 ± 5.17 and 9.3 ± 1.25 per hpf, respectively (P < .0001). An analysis to evaluate predictors of response associated a higher mean baseline esophageal intraepithelial eosinophil count with a greater reduction in mean count (P < .0001). CONCLUSIONS IL-5 is involved in the pathogenesis of EoE in children. Mepolizumab, an antibody against IL-5, reduces esophageal eosinophilic inflammation in these patients.

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.

Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes

BACKGROUND Hypereosinophilic syndromes (HESs) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid refractory or develop corticosteroid toxicity. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, showed corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with HESs. OBJECTIVE We evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES. METHODS MHE100901 is an open-label extension study. The primary end point was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of antimepolizumab antibodies were also explored. RESULTS Seventy-eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for ≥ 12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons. CONCLUSION Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES.

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

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.

Predictors of Uncontrolled Asthma in Adult and Pediatric Patients: Analysis of the Asthma Control Characteristics and Prevalence Survey Studies (ACCESS)

Background. Despite the availability of effective asthma treatments and evidence-based management guidelines focusing on asthma control, many patients have asthma that is inadequately controlled. The objective of this analysis was to identify risk factors for uncontrolled asthma among adult and pediatric patients. Methods. Two cross-sectional surveys assessing asthma control status were conducted between January 25 and May 2, 2008, among adult and pediatric patients with asthma. Participants completed a self-administered questionnaire including demographics, medical history, and current asthma medication use. In addition, participants completed either the Asthma Control Test (ACT) or Childhood ACT (C-ACT). Uncontrolled asthma was defined as a score of ≤19 on the ACT or C-ACT. Multiple logistic regression was used to identify factors related to uncontrolled asthma. Results. A sample of 64 primary care provider sites (35 for adults and 29 for pediatric patients) across the United States enrolled. One study enrolled 2238 adults (aged ≥18 years) and the other 2429 children (aged 4–17 years) with asthma. The patients were visiting their health care provider for a scheduled appointment for any reason. The overall prevalence of uncontrolled asthma was 58% and 46% in adult and pediatric patients, respectively. Multivariate analysis identified predictors of uncontrolled asthma in both adults and children including self-reported asthma severity, lack of adherence, and recent history of cold, flu, or sinus infection. The predictors of uncontrolled asthma seen only in adults were less education, insurance status, current smoker, body mass index (BMI) >30 kg/m2, and history of gastroesophageal symptoms. The predictors of uncontrolled asthma seen only in children were female aged 12–17 years, caregiver unemployment, and history of asthma exacerbation. Conclusions. A high proportion of patients with asthma seen in primary care settings are not well controlled. Recognition of specific predictors can signal who may be at higher risk of uncontrolled asthma and provide the opportunity for early interventions.

Body Mass Index and Response to Asthma Therapy: Fluticasone Propionate/Salmeterol versus Montelukast

We studied the relationship between body mass index (BMI) on responses to asthma therapy using a retrospective analysis of four previously reported clinical trials. Fluticasone propionate (FP)/salmeterol via Diskus 100/50 μg twice daily and montelukast (MON) 10 mg daily were compared. BMI was classified as underweight (less than 20 kg/m2), normal (20–24.9 kg/m2), overweight (25–29.9 kg/m2), obese-1 (30–34.9 kg/m2), obese-2 (35–39.9 kg/m2), or obese-3 (at least 40 kg/m2). Outcomes assessed included forced expiratory volume in one second (FEV1), asthma symptom score, and albuterol use. FP/salmeterol produced greater improvements compared to MON in each of the asthma outcomes studied over the entire BMI range at the week-12 endpoint, with statistically significant differences noted among normal, overweight, obese-1, and obese-3 subjects. The within-treatment responses to FP/salmeterol across BMI ranges at the week-12 endpoint was statistically significantly greater in normal compared to obese-3 for FEV1 and albuterol use, and in overweight compared to the obese-3 for each outcome studied. The within-treatment comparisons of MON across BMI ranges were significant for albuterol use in normal and underweight compared to obese-3 at the week-12 endpoint. Compared to subjects with normal BMI, the onset to peak FEV1 may require longer treatment exposure in the very obese. Treatment responses to FP/salmeterol were consistently greater compared to MON and persisted at higher BMI.