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Background Combination therapy with an inhaled corticosteroid (ICS) and long-acting β2 agonist (LABA) is recommended for patients with asthma symptomatic on ICS alone. However, there is ongoing debate regarding the risk-benefit ratio of using LABA in asthma. Objective To evaluate the effect of the addition of a novel LABA, vilanterol (VI), to a once-daily ICS, fluticasone furoate (FF), on the risk of severe asthma exacerbations in patients with uncontrolled asthma. Methods This randomised double-blind comparative study of variable duration (≥24–78 weeks) was designed to finish after 330 events (each patient's first on-treatment severe asthma exacerbation). 2019 patients with asthma aged ≥12 years with ≥1 recorded exacerbation within 1 year were randomised and received FF/VI 100/25 μg or FF 100 μg, administered once daily in the evening. The primary endpoint was time to first severe exacerbation; secondary endpoints were rate of severe asthma exacerbations per patient per year and change in trough evening forced expiratory volume in 1 s (FEV1) from baseline. Results Compared with FF, FF/VI delayed the time to first severe exacerbation (HR 0.795, 95% CI 0.642 to 0.985) and reduced the annualised rate of severe exacerbations (rate reduction 25%, 95% CI 5% to 40%). Significantly greater improvements in trough FEV1 (p

Background The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β 2 agonist vilanterol (VI) is in development for asthma and chronic obstructive pulmonary disease. Objective To assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma. Methods Patients (aged ≥12 years; on inhaled corticosteroid) were randomised (2:2:1) to FF/VI 100/25 µg or FF/VI 200/25 µg once daily in the evening, or fluticasone propionate (FP) 500 µg twice daily. Safety evaluations included adverse events (AEs), non-fasting glucose, potassium, 24-h urinary cortisol excretion, ophthalmic assessments, heart rate and pulse rate. Results On-treatment AEs were similar across groups (FF/VI 66–69%; 73% FP). Oral candidiasis/oropharyngeal candidiasis was more common with FF/VI (6–7%) than FP (3%). Twelve serious AEs were reported; one (worsening hepatitis B on FP) was considered drug related. Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 (ratios [95% CI] to FP ranged from 1.43 [1.11 to 1.84] to 1.67 [1.34 to 2.08]; p≤0.006), but not at Week 52 (ratios to FP were 1.05 [0.83 to 1.33] for FF/VI 100/25 µg and 1.09 [0.87 to 1.38] for FF/VI 200/25 µg). No clinically important changes in non-fasting glucose, potassium, QT interval corrected using Fridericia9s formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [T max ], Week 52) was significantly increased with FF/VI versus FP (3.4 bpm, 95% CI 1.3 to 5.6; p=0.002 [FF/VI 100/25 µg]; 3.4 bpm, 95% CI 1.2 to 5.6; p=0.003 [FF/VI 200/25 µg]). Mean heart rate (24-h Holter monitoring) decreased from screening values in all groups (0.2–1.1 bpm FF/VI vs 5 bpm FP; Week 52). Conclusions FF/VI (100/25 µg or 200/25 µg) administered once daily over 52 weeks was well tolerated by patients aged ≥12 years with asthma. The overall safety profile of FF/VI did not reveal any findings of significant clinical concern. ClinicalTrials.gov NCT01018186

Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24 h activity. FF is being developed as a once-daily treatment in combination with the long-acting β(2) agonist vilanterol trifenatate for asthma and chronic obstructive pulmonary disease.To determine the optimal dose(s) of FF for treating patients with asthma.An 8-week multicentre, randomised, double-blind study. 627 patients with persistent moderate-to-severe asthma, symptomatic on medium-dose inhaled corticosteroid therapy, were randomised to placebo, FF 200, 400, 600 or 800 μg (once daily in the evening using a novel dry powder inhaler), or fluticasone propionate 500 μg twice daily (via Diskus™/Accuhaler™). The primary efficacy measure was mean change from baseline in pre-dose evening forced expiratory volume in one second (FEV(1)). Other endpoints included morning and evening peak expiratory flow, and rescue/symptom-free 24 h periods.Each dose was significantly superior to placebo for the primary endpoint (p0.001) with efficacy at least similar to that reported with fluticasone propionate. There was no dose-response relationship across the FF doses studied. Peak expiratory flow improved in all groups (p0.001 vs placebo), and there were significant treatment effects on rescue/symptom-free 24 h periods with all active treatments. FF was generally well tolerated. The incidence of oral candidiasis was higher with FF 800 μg than placebo; pharmacokinetic and 24 h urinary cortisol analyses confirmed a higher systemic exposure of FF at this highest dose level.FF doses800 μg have a favourable therapeutic index. The absence of an efficacy dose response suggests that 200 μg is an appropriate dose in patients with moderate persistent asthma. CLINICALTRIALS.GOV IDENTIFIER: NCT00603746.

The natural history of asthma involves relatively stable periods that are often punctuated by significant exacerbations of symptoms. There are many aetiologies that may lead to an increase in asthma severity including respiratory infection (bacterial/viral), allergens, irritants, and occupational exposures. Each trigger probably acts through different mechanisms, but a final common pathway of multicellular inflammation, enhanced bronchial responsiveness, and airflow obstruction is a likely consequence. This review discusses the most common causes of asthma exacerbations with a focus on their microbiology and immunopathogenesis. Through an understanding of underlying causes of asthma exacerbations, treatments with increased effectiveness may be developed, and it is these future developments that may directly influence the morbidity and mortality of the disease.

BACKGROUND: Cysteinyl leukotriene release in association with airway inflammation is a feature of clinical asthma. The acute effects of montelukast (MK-0476), a potent, orally administered, specific cysteinyl leukotriene receptor antagonist, on airways obstruction was assessed in patients with mild to moderately severe asthma. METHODS: Twenty two asthmatic subjects were randomised to receive montelukast, 100 mg or 250 mg, or placebo in a double blind, three period, crossover trial. Ten of the patients were using concomitant inhaled corticosteroids. RESULTS: Montelukast increased the forced expiratory volume in one second (FEV1) from predose baseline values compared with placebo, the percentage point differences between montelukast and placebo being 8.6% (95% CI 3.6 to 13.6) and 8.5% (95% CI 3.5 to 13.5) for the 100 mg and 250 mg doses, respectively. CONCLUSION: Single oral doses of montelukast 100 mg and 250 mg produced significant increases in FEV1 irrespective of the concurrent use of inhaled corticosteroids in asthmatic subjects with airflow limitation.

Background A double-blind, randomised, placebo-controlled, 60-week study of mepolizumab (300 mg every 4 weeks) in eosinophilic granulomatosis with polyangiitis (EGPA) is being sponsored by GlaxoSmithKline in collaboration with the National Institute of Allergy and Infectious Diseases (NIH) in the US. It is critical to ensure definition of the appropriate EPGA diagnostic criteria and study outcomes for this global study. Objectives To present the study design, criteria for selection of the study population and study endpoints. Methods EGPA researchers in North America and Europe were consulted on the critical outcomes required to demonstrate clinical benefit in the treatment of EGPA and the appropriate patient population for investigation in a clinical trial. Results In this study we modified the American College of Rheumatology criteria for the classification of EGPA by addition of further criteria to ensure that recruited subjects have a definite diagnosis of EGPA determined by the presence of key manifestations of this condition, i.e., asthma plus eosinophilia with two of nine further features of EGPA. Eligible subjects are required to have a history of relapsing or refractory disease and will continue on background standard of care therapy including corticosteroids, with or without immunosuppressive therapy. Key outcomes to demonstrate benefit in the treatment of EGPA were identified as duration of remission (accrued and sustained), reduction in risk of relapse and reduction in corticosteroid usage. Based on this, co-primary endpoints are: i) total accrued duration of remission, where remission = BVAS of zero plus prednisolone dose ≤4 mg/day and ii) proportion of subjects who are in remission at both Weeks 36 and 48 of the 52-week study treatment period. Key secondary endpoints are: i) time to first relapse; ii) average daily prednisolone dose during the last 4 weeks of treatment, iii) the proportion of subjects who achieve remission within the first 24 weeks of the study and then stay in remission. Conclusions This double-blind, randomised study is adopting modified EGPA diagnostic criteria and novel endpoints with the objective of investigating the efficacy and safety of mepolizumab compared to placebo in subjects with relapsing or refractory EGPA, receiving standard of care therapy. Patient recruitment is being initiated in 2014. Disclosure of Interest R. Philipson Employee of: GlaxoSmithKline., J. Anderson Employee of: GlaxoSmithKline., J. Brown Employee of: GlaxoSmithKline., W. Busse Consultant for: GlaxoSmithKline., M. Cid Grant/research support: Centocor., Consultant for: GlaxoSmithKline, Roche Pharma., Speakers bureau: BMS., G. Gleich Consultant for: GlaxoSmithKline., W. Gross Consultant for: GlaxoSmithKline., L. Guillevin Consultant for: GlaxoSmithKline., Speakers bureau: Roche Pharma., H. Ortega Employee of: GlaxoSmithKline., D. Jayne Grant/research support: Roche/Genetech, Genzyme., Consultant for: Chemcocentryx, GlaxoSmithKline, Rocher/Genentech, Takeda., Speakers bureau: GlaxoSmithKline, Roche/Genentech., C. Pagnoux Consultant for: GlaxoSmithKline., C. Savage Employee of: GlaxoSmithKline., P. Weller Consultant for: GlaxoSmithKline., M. Wechsler Consultant for: GlaxoSmithKline, Merck, Boehringer Ingelheim, Novartis, Cytos, Medimmune, Teva. DOI 10.1136/annrheumdis-2014-eular.1764

We thank Dr Lipworth for his response to our article on the safety and tolerability of fluticasone furoate/vilanterol (FF/VI) combination in asthma,1 in which he specifically discusses effects on urinary cortisol. We acknowledge the limitations of urinary cortisol assessment; however, as outlined in the online supplement, the urinary cortisol population in our study specifically excluded subjects with an incomplete urine collection and/or 24-h urinary creatinine levels below the lower limit of the threshold range. Thus, our data are not confounded …

A double dose is not enough The management of asthma consists of the regular use of anti-inflammatory medications and an action plan for worsening of symptoms or an asthma exacerbation. Guidelines for the treatment of asthma have recommended doubling the dose of maintenance inhaled corticosteroids for deteriorations in asthma control that are not responding to β agonist rescue treatment in the usual manner.1,2 Although this approach has been advocated, evidence to support its effectiveness has been largely wanting. In this issue of Thorax FitzGerald and colleagues3 and members of the Canadian Asthma Exacerbation Study Group evaluated this approach. They identified 290 patients with well characterised asthma, all of whom had a history of at least one previous asthma exacerbation—defined as an increase in symptoms and the need for a change in medication not more than 12 months and not less than 1 month before the start of the run in period. During the run in period all subjects were maintained on their usual dose of inhaled corticosteroids. Subjects were then either assigned to maintenance treatment and received their usual dose of budesonide (100, 200, or 400 μg twice daily) plus a placebo inhaler to be used twice a day with an exacerbation, or were on the same doses of inhaled corticosteroid plus an inhaler containing active inhaled corticosteroid which therefore doubled their maintenance dose of inhaled corticosteroids during the exacerbation. An …