Efficacy of add-on mepolizumab in adolescents with severe eosinophilic asthma.

Adolescents (12-17 years of age) with severe eosinophilic asthma experience frequent exacerbations and reduced lung function leading to poor health-related quality of life. Mepolizumab is approved for add-on maintenance therapy in patients with severe eosinophilic asthma ≥ 6 years of age in the EU and ≥ 12 years of age in other regions (including the USA), based on a Phase II/III program demonstrating reduced exacerbation rates with 4-weekly treatment. A total of 34 adolescent patients were recruited across the Phase III mepolizumab trials. Consistent with outcomes in the overall population, there was a reduction in the annual rate of clinically significant exacerbations, along with a reduction in blood eosinophil counts in response to mepolizumab in adolescent patients. The safety profile in adolescent patients was consistent with that seen in the overall population. Data from the Phase III clinical development program provide evidence for comparable efficacy and safety of mepolizumab between adolescents with severe eosinophilic asthma and the overall population. Clinical trial registration DREAM, NCT01000506 [MEA112997]; MENSA, NCT01691521 [MEA115588]; SIRIUS, NCT01691508 [MEA115575]; MUSCA, NCT02281318 [200862]; COSMOS, NCT01842607 [MEA115661].

Association of depressive symptoms with health status and markers of uncontrolled severe asthma.

Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p < 0.001). Eighty-nine percent of the patients in the severe BDI-II category had poorly controlled asthma (ACQ-5 score ≥ 1.5) compared with 63% in the minimal category (p < 0.001). Conclusion: Increased severity of depressive symptoms was associated with worse respiratory-related quality of life and asthma control in the patients with severe eosinophilic asthma. These findings highlight the need for a multidimensional approach for the management of uncontrolled asthma, including timely identification of depressive symptoms. Additional research is needed to further explore the interactions between the two common conditions.Clinical trials NCT01691521 and NCT01619508, www.clinicaltrials.gov.

Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma.

BACKGROUND: Studies show that mepolizumab can reduce the frequency of clinically significant exacerbations in patients with severe eosinophilic asthma, compared with placebo. However, important events such as hospitalizations and emergency room visits are rare and difficult to characterize in single studies. OBJECTIVE: We sought to compare hospitalization or hospitalization and/or emergency room visit rates in patients with severe eosinophilic asthma treated with mepolizumab or placebo in addition to standard of care for at least 24 weeks. METHODS: This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. PubMed and the GSK Clinical Study Register were searched for suitable studies. The primary end points were the rate of exacerbations requiring hospitalization and the rate of exacerbations requiring hospitalization/emergency room visit. The proportion of patients with 1 or more event was also assessed. All mepolizumab doses were combined and individual patient-level data were analyzed. RESULTS: Four studies (n = 1388) were eligible for inclusion. Mepolizumab significantly reduced the rate of exacerbations requiring hospitalization (relative rate, 0.49; 95% CI, 0.30-0.80; P = .004) and hospitalization/emergency room visit (relative rate, 0.49; 95% CI, 0.33-0.73; P < .001) versus placebo. Significant reductions of 45% and 38% were also observed for the proportion of patients experiencing 1 or more hospitalization and hospitalization and/or emergency room visit, respectively. CONCLUSIONS: Mepolizumab approximately halved exacerbations requiring hospitalization and/or emergency room visits compared with placebo in patients with severe eosinophilic asthma. This treatment addresses a key outcome in a patient population with a high unmet need (GSK Study 204664).

Long-term Efficacy and Safety of Mepolizumab in Patients With Severe Eosinophilic Asthma: A Multi-center, Open-label, Phase IIIb Study.

PURPOSE: Patients with severe eosinophilic asthma often experience recurrent asthma exacerbations despite intensive inhaled corticosteroid therapy. In 2 previous double-blind studies (MENSA [NCT01691521] and SIRIUS [NCT01691508]), treatment with intravenous or subcutaneous mepolizumab was associated with significantly reduced annualized exacerbation rates and oral corticosteroid (OCS) requirements compared with placebo. The purpose of this study was to assess the long-term safety and efficacy of subcutaneous mepolizumab treatment in patients with severe eosinophilic asthma. METHODS: COSMOS was a 52-week, open-label extension study in patients who received mepolizumab or placebo in MENSA or SIRIUS. Patients received subcutaneous mepolizumab regardless of prior treatment allocation and continued to receive appropriate standard-of-care asthma therapy throughout. The primary objective was to assess the long-term safety of mepolizumab; end points included adverse events (AEs) and serious AEs (SAEs). Efficacy assessments included the annualized exacerbation rate and durability of response (defined as the exacerbation rate and OCS dose reduction when combined with MENSA and SIRIUS data, respectively). FINDINGS: In total, 558 (86%; previous mepolizumab: 358; previous placebo: 200) and 94 (14%; previous mepolizumab: 58, previous placebo: 36) patients experienced on-treatment AEs and SAEs, respectively. No fatal AEs were reported. Totals of 13 (2%) and 29 (4%) patients experienced systemic and local site reactions, respectively. There were no reports of mepolizumab-related anaphylaxis. Mepolizumab treatment was shown to exert a durable response, with patients who previously received mepolizumab in MENSA or SIRIUS maintaining reductions in exacerbation rate and OCS dosing throughout COSMOS. Patients who previously received placebo in MENSA or SIRIUS demonstrated improvements in these end points following treatment with mepolizumab in COSMOS. IMPLICATIONS: These data demonstrate a favorable safety profile of mepolizumab and indicate a durable and stable effect over time, supporting long-term treatment in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT01842607.

Retrospective cohort analysis of healthcare claims in the United States characterising asthma exacerbations in paediatric patients.

BACKGROUND: Asthma is the most common chronic disease in childhood and places a significant burden on public and private health systems. This retrospective cohort analysis utilised administrative healthcare claims data (US Clinformatics™ Multiplan database; compliant with the US Department of Health & Human Services Health Insurance Portability and Accountability Act) to characterise asthma exacerbations requiring intervention in a US paediatric patient population. METHODS: Patients aged > 1-17 years with a recorded asthma diagnosis and receiving treatment were identified in the US Clinformatics™ Multiplan database over a 9-year period (2004-2012). Both incident and prevalent cases of asthma were included, with the most recently recorded asthma diagnosis designated as the index date. The 12-month period following the index date was analysed for asthma exacerbations, defined as an event requiring treatment with systemic corticosteroid or resulting in an asthma-related hospitalisation or emergency department visit. RESULTS: Data from 734,114 children with asthma (41.5 % females, 58.5 % males) were analysed, of this cohort 34.4 % experienced ≥ 1 exacerbation during the follow-up period. The proportion who experienced ≥ 1 exacerbation increased from 28.9 % in 2004 to 36.3 % in 2012, based on the reported index date. Their mean annual exacerbation frequency was 1.4; 85.8 % of exacerbations were defined by systemic corticosteroids use. A consistent trend of increased exacerbation incidence in the fall and early winter was observed, in particular exacerbations defined by systemic corticosteroid use. A greater proportion of asthma-related hospitalisations were associated with younger age. CONCLUSIONS: Approximately one-third of children experienced ≥ 1 exacerbation in real-world clinical practice. A targeted treatment approach with a focus on those with a history of recurrent exacerbations is recommended to improve asthma control. This targeted approach could also minimise the frequent systemic corticosteroid exposure particularly at an early age when side effects of systemic corticosteroids are more pronounced.

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.

Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.

OBJECTIVE: Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor, which is mainly expressed on eosinophils. Eosinophils are key cells in the inflammatory cascade of various diseases, including asthma. This study investigated the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between exposure of mepolizumab subcutaneous (SC) administration and blood eosinophil reduction compared with intravenous (IV) administration in adult subjects with asthma. METHODS: In this multi-center, randomized, open-label, parallel-group, repeat-dose study, 70 adult subjects received one of four possible treatment regimens: mepolizumab 12.5, 125, or 250 mg SC or 75 mg IV. In addition to analyzing the dose and PK/PD relationship, absolute bioavailability, safety, tolerability, and incidence of anti-mepolizumab antibodies were evaluated. RESULTS: Blood eosinophil levels decreased in a dose-dependent manner with the lowest (12.5 mg) dose clearly differentiating from the other doses. A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50% and 90% of maximal blood eosinophil inhibition were 11 mg (95% confidence interval (CI): 5.19 - 16.85) and 99 mg (95% CI: 47 - 152), respectively. The route of administration did not affect the exposure-response relationship. The estimated mepolizumab SC absolute bioavailability (arm) was 74% (90% CI: 54 - 102%). The safety profile of mepolizumab was favorable. CONCLUSIONS: A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed. The subcutaneous absolute bioavailability was 74%. The route of administration did not affect the mepolizumab exposure eosinophil response relationship.

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.).

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. George's 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.).

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.

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.

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.

Adding montelukast to fluticasone propionate/salmeterol for control of asthma and seasonal allergic rhinitis.

Limited information exists comparing fluticasone propionate/salmeterol combination (FSC) versus montelukast (MON) in patients with coexistent asthma and allergic rhinitis. The purpose of this study was to compare the addition of MON to patients receiving FSC on asthma control while experiencing asthma and allergy symptoms. Additionally, the effect of fluticasone propionate aqueous nasal spray (FPANS) and MON were assessed in allergic rhinitis control. Symptomatic patients (n = 1385) with asthma and seasonal allergic rhinitis were randomized to receive FSC, 100/50 micrograms twice daily; FSC twice daily + FPANS, 200 micrograms once daily; FSC twice daily + MON, 10 mg once daily; or MON once daily for 4 weeks during the allergy pollen season. Patients recorded peak expiratory flow, rescue albuterol use, and asthma and rhinitis symptoms. No additional improvements in overall asthma control were seen when MON was added to FSC. Treatment with FSC produced significant (p < 0.001) improvements in all clinical and patient-reported measures versus MON. FSC + FPANS was superior to FSC + MON (p < or = 0.001) in improving daytime and nighttime total nasal symptom scores. Adverse events were similar. In patients with asthma and allergic rhinitis, adding MON to FSC provided no additional benefit in asthma control. FSC resulted in superior improvement in asthma control compared with MON. FPANS also provided superior nasal symptom control versus MON in allergic patients treated with FSC for asthma. Optimal disease control in patients with asthma and allergic rhinitis should be achieved by the most effective therapy directed toward each disease component.

Comparative effect of body mass index on response to asthma controller therapy.

Increases in body mass index (BMI) are reported to influence asthma severity and response to treatment. This analysis was designed to explore whether increasing BMI altered the comparative response to treatment with either fluticasone propionate (FP) or montelukast. Two double-blind, randomized, parallel-group trials of 12-weeks duration comparing FP, 88 micrograms, twice daily or montelukast, 10 mg, daily were evaluated. Subjects with mild-moderate persistent asthma were retrospectively stratified by BMI of <20 kg/m(2) (underweight), 20-24.9 kg/m(2) (normal weight), 25-29.9 kg/m(2) (overweight), and > or =30 kg/m(2) (obese). Outcomes included mean changes in forced expiratory volume in 1 second (FEV(1)) and morning peak flow, daily albuterol use, and daily symptom scores. There were 1052 subjects evenly distributed between FP and montelukast by baseline parameters, including BMI. FP was statistically superior to montelukast for all BMI categories of normal, overweight, and obese subjects for FEV(1) (p < 0.008), morning peak flow (p < 0.002), albuterol use (p < 0.02), and symptom scores (p < 0.05). FP produced a significantly greater clinical response for normal, overweight, and obese subjects compared with montelukast. Irrespective of BMI, FP appears to be the more effective asthma controller therapy.

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 microg twice daily and montelukast (MON) 10 mg daily were compared. BMI was classified as underweight (less than 20 kg/m(2)), normal (20-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), obese-1 (30-34.9 kg/m(2)), obese-2 (35-39.9 kg/m(2)), or obese-3 (at least 40 kg/m(2)). Outcomes assessed included forced expiratory volume in one second (FEV(1)), 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 FEV(1) 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 FEV(1) 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.

Low-dose fluticasone propionate with and without salmeterol in steroid-naïve patients with mild, uncontrolled asthma.

BACKGROUND: The role of combination ICS/LABA as initial controller therapy in mild, persistent asthma is uncertain. Therefore, the objective of this study was to compare the efficacy of initial controller therapy with fluticasone propionate (FP) 100 microg twice daily to the efficacy of fluticasone propionate/salmeterol xinafoate (FSC) 100/50 microg twice daily in patients with persistent asthma symptoms while using as-needed SABA alone. METHODS: This randomized, double-blind, parallel-group study was conducted at 45 general practice and 15 specialist centers. A total of 526 adult patients were randomized to receive FP or FSC for 24 weeks. The primary efficacy endpoint was change in morning peak expiratory flow (PEF) from baseline. Secondary efficacy endpoints included symptom- and rescue-free days; asthma exacerbation rate; asthma-related health-care utilization; and the onset of effect. Safety was assessed by monitoring adverse events. RESULTS: Mean morning PEF was significantly greater in the FSC versus the FP group (P<0.001); this greater effect was evident as early as the first week of treatment (P<0.001). The percentages of symptom-free days and rescue-free days in the FSC group were 7.7% (P=0.009) and 8.4% (P=0.001) higher than the FP group, respectively. Trends toward lower exacerbation-related health care-utilization for FSC versus FP were not statistically significant and exacerbation rates were not significantly different. The incidence of adverse events was low with both treatments. CONCLUSIONS: :Treatment with FSC was a more effective initial controller therapy than FP monotherapy in ICS-naïve patients who had uncontrolled asthma while using as-needed SABA alone.

Beta2-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).

Effects of fluticasone propionate and salmeterol hydrofluoroalkane inhalation aerosol on asthma-related quality of life.

BACKGROUND: Current asthma guidelines emphasize domains of impairment and risk for assessing severity and control, noting the need to consider separately the effects of asthma on asthma quality of life and functional capacity. Proper treatment to control asthma should result in improvements in patient well-being and functional status. OBJECTIVE: To assess asthma-related quality of life after treatment with combination fluticasone propionate and salmeterol delivered via hydrofluoroalkane 134a metered-dose inhaler compared with the individual components alone. METHODS: Asthma-related quality of life was assessed as part of two 12-week, randomized, double-blind, placebo-controlled clinical trials comparing the fluticasone propionate-salmeterol combination administered via a single metered-dose inhaler with salmeterol, fluticasone propionate, and placebo administered via traditional chlorofluorocarbon metered-dose inhaler. The Asthma Quality of Life Questionnaire was completed at baseline and end point. Score changes, overall and for the 4 separate domains, were compared within and among the treatment groups. RESULTS: A total of 720 of 725 patients completed a baseline Asthma Quality of Life Questionnaire and were included in the analyses. In both studies, all mean scores improved significantly from baseline with the fluticasone propionate-salmeterol combination, with significantly greater improvement in the overall score compared with salmeterol alone, fluticasone propionate alone, and placebo groups. Improvements with the combination were also clinically meaningful compared with changes with salmeterol and placebo in both studies and with fluticasone propionate in study 1. CONCLUSIONS: Treatment with combination fluticasone propionate and salmeterol delivered via hydrofluoroalkane metered-dose inhaler resulted in significantly greater improvements in asthma-related quality of life compared with individual components and placebo administered via traditional chlorofluorocarbon metered-dose inhaler.