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Korn S.,Mainz University Hospital | Kerwin E.,Southern Research Institute | Atis S.,Mersin University | Amos C.,Novartis | And 2 more authors.
Respiratory Medicine | Year: 2011

Background: Indacaterol is a novel, inhaled once-daily ultra-long-acting β2-agonist for the treatment of COPD. Methods: This 12-week randomised, parallel-group study compared the efficacy of indacaterol 150 μg once-daily to salmeterol 50 μg twice-daily in patients with moderate-to-severe COPD. Assessments included FEV1 standardised area under curve (AUC) from 5 min to 11 h 45 min at Week 12 (primary endpoint), 24-h trough FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (key secondary endpoint), FEV1 and FVC measured over 24-h, transition dyspnoea index (TDI) and rescue medication use. Results: Of 1123 patients randomised 92.1% completed. Mean ± SD age was 62.8 ± 8.78 years, post-bronchodilator FEV1 51.8 ± 12.32% predicted, FEV1/FVC 50.6 ± 9.54%. At Week 12, FEV1 AUC 5 min-11 h 45 min for indacaterol was statistically superior (p < 0.001) to salmeterol (adjusted mean difference [95% CI] 57 [35, 79] mL), as was 24-h trough FEV1 (60 [37, 83] mL, p < 0.001). Indacaterol also showed statistical superiority over salmeterol in terms of FEV1 and FVC measured over 24-h at Week 12. For TDI at Week 12, the mean total score was statistically superior for indacaterol versus salmeterol (difference 0.63 [0.30, 0.97], p < 0.001), as was the percentage of patients with a clinically relevant (i.e., ≥1 point) change from baseline (69.4% vs 62.7%, p < 0.05). For rescue medication, patients on indacaterol used fewer puffs/day (difference -0.18 [-0.36, 0.00] puffs/day, p < 0.05) and had a greater percentage of days with no rescue use (difference 4.4 [0.6, 8.2], p < 0.05). Conclusion: Once-daily indacaterol provided statistically superior bronchodilation with an improvement in breathlessness and rescue use compared with twice-daily salmeterol. NCT00821093 © 2010 Elsevier Ltd. All rights reserved.

Bateman E.D.,University of Cape Town | Buhl R.,Mainz University Hospital | O'Byrne P.M.,McMaster University | Humbert M.,University Paris - Sud | And 7 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Identifying patients at risk of future severe asthma exacerbations, those whose asthma might be less treatment responsive, or both might guide treatment selection. Objective We sought to investigate predictors for failure to achieve Global Initiative for Asthma (GINA)-defined good current asthma control and severe exacerbations on treatment and to develop a simple risk score for exacerbations (RSE) for clinical use. Methods A large data set from 3 studies comparing budesonide/formoterol maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting β2-agonist therapy was analyzed. Baseline patient characteristics were investigated to determine dominant predictors for uncontrolled asthma at 3 months and for severe asthma exacerbations within 12 months of commencing treatment. The RSE, right censored at 6 months to include all 3 studies, was based on the dominant predictors for exacerbations in two thirds of the data set and validated in one third. Results Patients (n = 7446) whose symptoms were not controlled on GINA treatment steps 3 and 4 and with 1 or more exacerbations (as judged by a clinician based on patient records, history, or both) in the previous year were included. On multivariate analysis, GINA step, reliever use, postbronchodilator FEV1, and 5-item Asthma Control Questionnaire score were dominant (all P <.001) predictors for both the risk of uncontrolled asthma and severe exacerbations. Additional dominant predictors for uncontrolled asthma were smoking status and asthma symptom scores and an additional predictor for severe exacerbation was body mass index. An exponential increase in risk was observed with increments in RSE based on 5 selected predictors for exacerbations. Conclusion Risk of uncontrolled asthma at 3 months and a severe exacerbation within 12 months can be estimated from simple clinical assessments. Prospective validation of these predictive factors and the RSE is required. Use of these models might guide the management of asthmatic patients. © 2014 American Academy of Allergy, Asthma & Immunology.

Paggiaro P.,University of Pisa | Halpin D.M.G.,Royal Devon and Exeter Hospital | Buhl R.,Mainz University Hospital | Engel M.,Boehringer Ingelheim | And 4 more authors.
Journal of Allergy and Clinical Immunology: In Practice | Year: 2016

Background: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, has demonstrated efficacy in patients with asthma who were symptomatic despite treatment with medium- to high-dose inhaled corticosteroids (ICS). Objective: The objective of this study was to evaluate the efficacy and safety of once-daily tiotropium Respimat (5 μg or 2.5 μg), compared with placebo Respimat, as add-on therapy to low- to medium-dose ICS for adults with symptomatic asthma. Methods: A phase III, double-blind, placebo-controlled trial was conducted (NCT01316380). Adults with symptomatic asthma receiving low- to medium-dose ICS (200-400 μg budesonide or equivalent dose) and a pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥60% and ≤90% of predicted normal were randomized to 12 weeks of treatment with once-daily tiotropium Respimat 5 μg or 2.5 μg, or placebo Respimat, as add-on therapy to ICS. The primary endpoint was peak FEV1(0-3h) response. Results: In total, 464 patients were randomized (61% female; mean age 43 years; mean baseline FEV1 78% of predicted normal). After 12 weeks, both tiotropium Respimat doses were superior to placebo (adjusted mean difference from placebo: 5 μg, 128 mL; 2.5 μg, 159 mL; both P <.001). Both doses of tiotropium Respimat were also superior to placebo with regard to the secondary endpoints of adjusted mean trough FEV1 and FEV1 area under the curve(0-3h) responses, and the other endpoints of morning and evening peak expiratory flow. Adverse events were comparable across the treatment groups. Conclusions: Once-daily tiotropium Respimat add-on therapy to low- to medium-dose ICS in adults with symptomatic asthma is an efficacious bronchodilator, and its safety and tolerability are comparable with those of placebo Respimat. © 2015 The Authors.

Pavord I.D.,University of Leicester | Korn S.,Mainz University Hospital | Howarth P.,Southampton General Hospital | Bleecker E.R.,Center for Genomics and Personalized Medicine | And 4 more authors.
The Lancet | Year: 2012

Background Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway infl ammation. Early studies suggest that inhibition of eosinophilic airway infl ammation with mepolizumab- a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish effi cacy, 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 infl ammation. 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 09% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratifi ed by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically signifi cant asthma exacerbations, which were defi ned 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, 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 signifi cant. The rate of clinically signifi cant exacerbations was 240 per patient per year in the placebo group, 124 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<00001), 146 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=00005), and 115 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<00001). Three patients died during the study, but the deaths were not deemed to be related to treatment. Interpretation Mepolizumab is an eff ective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. Funding GlaxoSmithKline.

Wedzicha J.A.,Imperial College London | Buhl R.,Mainz University Hospital | Lawrence D.,Novartis | Young D.,Novartis
Respiratory Medicine | Year: 2015

Methods Six-month data were pooled from three randomized, double-blind, and placebo-controlled studies: indacaterol 300 μg versus placebo (1 year); indacaterol 150 μg and 300 μg versus placebo (6 months); and indacaterol 150 μg versus placebo (6 months). All treatments were administered oncedaily. Data from other treatment groups were excluded. All three studies enrolled patients aged ≥40 years with moderate-to-severe COPD and smoking history ≥20 pack-years. Time to exacerbation and exacerbation rate were analyzed.Results Overall, the pooled data set included 2716 patients (indacaterol 150 μg [n = 746], indacaterol 300 μg [n = 819], placebo [n = 1151]). Both indacaterol doses 150 and 300 μg significantly reduced the COPD exacerbation rates compared with placebo (Rate ratios, RR [95% Confidence Interval, CI]: 0.69 [0.55-0.87], 0.71 [95% CI: 0.57-0.88] respectively; both p = 0.002). Over 6 months, indacaterol 150 and 300 μg also significantly prolonged the time to first moderate-to-severe exacerbation versus placebo (Hazard ratios, HR [95% CI]: 0.74: [0.59-0.93], p = 0.009; 0.73 [0.59-0.90], p = 0.004, respectively). At months 3 and 6, clinically relevant improvements in lung function versus placebo were observed with indacaterol 150 μg (Least squares mean treatment differences: Month 3 = 170 mL; Month 6 = 160 mL) and 300 μg (170 mL at both time-points; all p < 0.001).Conclusions In this pooled analysis, both indacaterol doses, 150 and 300 μg, were associated with significant reductions in exacerbations and significant improvements in bronchodilation versus placebo. The results suggest once-daily indacaterol is an effective treatment option for providing sustained bronchodilation and preventing exacerbations in patients with COPD.Background In patients with COPD, exacerbations are associated with poor quality of life and may shorten survival. Prevention of exacerbations is, therefore, a key objective in COPD management. Indacaterol, a once-daily ultra-long-acting β2-agonist, has been shown to reduce exacerbations in various studies. This pooled analysis evaluated the effect of indacaterol on exacerbations versus placebo. © 2014 Elsevier Ltd. All rights reserved.

Buhl R.,Mainz University Hospital | Banerji D.,Novartis
International Journal of COPD | Year: 2012

Bronchodilators are central in the symptomatic management of chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) are the main classes of long-acting bronchodilators. To date, tiotropium is the only once-daily LAMA available for the treatment of COPD. Glycopyrronium is a novel LAMA, currently in development for COPD. Phase II studies have shown that glycopyrronium 50 μg once daily provides clinically significant 24-hour bronchodilation with a rapid onset of action, which is faster than that of tiotropium, and a favorable safety and tolerability profile. The Phase III GLycopyrronium bromide in COPD airWays (GLOW) program has now confirmed the long-term efficacy and tolerability of glycopyrronium 50 μg once daily. The three studies included in this program have further shown that the effect of glycopyrronium versus placebo is similar to that of tiotropium in reducing dyspnea and the risk of exacerbations, as well as improving lung function, exercise tolerance, and health status in patients with COPD. The safety profile of glycopyrronium is also similar to that of tiotropium in terms of overall incidence of adverse events and muscarinic side effects. Glycopyrronium could be an alternative choice to tiotropium, and like tiotropium, has the potential to be used as a monotherapy or combination therapy. Phase II studies have shown that a fixed-dose combination of glycopyrronium and the 24-hour LABA indacaterol, produces rapid and sustained bronchodilation compared with indacaterol monotherapy in patients with COPD. Phase III studies are currently ongoing to assess the long-term efficacy and safety of this combination. © 2012 Buhl and Banerji, publisher and licensee Dove Medical Press Ltd.

Beeh K.-M.,Insaf Respiratory Research Institute | Korn S.,Mainz University Hospital | Beier J.,Insaf Respiratory Research Institute | Jadayel D.,Novartis | And 3 more authors.
Respiratory Medicine | Year: 2014

Introduction QVA149 is a novel, inhaled, once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2- agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the effects of QVA149 on exercise tolerance, hyperinflation, lung function and lung volumes versus placebo and tiotropium. Methods Patients with moderate-to-severe COPD were randomized to QVA149 110/50 μg, placebo or tiotropium 18 μg once daily in a blinded, 3-period crossover study for 3 weeks. The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo. Results Eighty-five patients were randomized; 86% completed the study. QVA149 significantly improved exercise endurance time at Day 21 compared with placebo (least squares mean treatment difference 60 s [p = 0.006]). No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found. Dynamic inspiratory capacity (IC) at exercise isotime, trough forced expiratory volume in 1 s, residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study. The safety profiles were similar across groups. Conclusions In patients with moderate-to-severe COPD, once-daily QVA149 significantly improved exercise endurance time compared with placebo which was associated with sustained reductions of lung hyperinflation as indicated by significant improvement in IC at rest and during exercise. Trial registration: NCT01294787. Take home message: Dual bronchodilation with QVA149 decreases lung hyperinflation and improves exercise tolerance and lung function in patients with moderate-to-severe COPD. © 2014 Elsevier Ltd. All rights reserved.

Korn S.,Mainz University Hospital | Hubner M.,Mainz University Hospital | Jung M.,Mainz University Hospital | Blettner M.,Mainz University Hospital | Buhl R.,Mainz University Hospital
Respiratory Research | Year: 2013

Background: Vitamin D has effects on the innate and adaptive immune system. In asthmatic children low vitamin D levels are associated with poor asthma control, reduced lung function, increased medication intake, and exacerbations. Little is known about vitamin D in adult asthma patients or its association with asthma severity and control.Methods: Clinical parameters of asthma control and 25-hydroxyvitamin D (25(OH)D) serum concentrations were evaluated in 280 adult asthma patients (mean ± SD: 45.0 ± 13.8 yrs., 40% male, FEV1 74.9 ± 23.4%, 55% severe, 51% uncontrolled).Results: 25(OH)D concentrations in adult asthmatics were low (25.6 ±11.8 ng/ml) and vitamin D insufficiency or deficiency (vitamin D <30 ng/ml) was common (67%). 25(OH)D levels were related to asthma severity (intermittent: 31.1 ± 13.0 ng/ml, mild: 27.3 ± 11.9 ng/ml, moderate: 26.5 ± 12.0 ng/ml, severe: 24.0 ± 11.8 ng/ml, p = 0.046) and control (controlled: 29.5 ± 12.5 ng/ml, partly controlled 25.9 ± 10.8 ng/ml, uncontrolled: 24.2 ± 11.8 ng/ml, p = 0.030). The frequency of vitamin D insufficiency or deficiency was significantly higher in patients with severe or uncontrolled asthma and was associated with a lower FEV1 (vitamin D <30 vs. ≥30 ng/ml 2.3 ± 0.9 L vs. 2.7 ± 1.0 L, p = 0.006), higher levels of exhaled NO (45 ± 46 ppb vs. 31 ± 37 ppb, p = 0.023), a higher BMI (28.3 ± 6.2 vs. 25.1 ± 3.9, p < 0.001), and sputum eosinophilia (5.1 ± 11.8% vs. 0.5 ± 1.0%, p = 0.005). The use of oral corticosteroids or sputum eosinophilia was associated with a 20% or 40% higher risk of vitamin D insufficiency or deficiency.Conclusions: 25(OH)D levels below 30 ng/ml are common in adult asthma and most pronounced in patients with severe and/or uncontrolled asthma, supporting the hypothesis that improving suboptimal vitamin D status might be effective in prevention and treatment of asthma. © 2013 Korn et al.; licensee BioMed Central Ltd.

Korn S.,Mainz University Hospital | Buhl R.,Mainz University Hospital
Respiratory Medicine | Year: 2012

Recommended treatment for moderate to severe asthma is the combination of an inhaled corticosteroid and a long-acting beta2-agonist. The present study was designed to evaluate the efficacy of a newly developed fixed combination of ciclesonide and formoterol in comparison to the marketed fixed combination of fluticasone and salmeterol in patients with moderate asthma. This was a phase II, multi-centre, randomized, parallel-group, double-blind, double-dummy study. After a 2-week run-in period, 160 patients with moderate asthma were randomized to a 6-week treatment with ciclesonide/formoterol 320/9 μg bid (CIC/F) or fluticasone propionate/salmeterol 250/50 μg bid (FP/S), both delivered as powder formulations. The primary outcome FEV1 increased during treatment by 0.356 L in the CIC/F group and by 0.288 L in the FP/S group (p < 0.0001). The increases were statistically significant and clinically relevant. The between-treatment analysis demonstrated non-inferiority of CIC/F to FP/S treatment (p < 0.0001). A significant improvement from baseline in lung function, symptom score and rescue medication use was observed in both groups at all time points. No differences were observed between treatments in the frequency of adverse events and overnight urinary cortisol/creatinine ratio. The studied fixed combination of ciclesonide/formoterol is not inferior to the marketed fixed combination of fluticasone/salmeterol in terms of efficacy and tolerability. © 2011 Elsevier Ltd. All rights reserved.

Buhl R.,Mainz University Hospital | Dunn L.J.,Clinical Research of West Florida | Disdier C.,San Pedro Of Alcantara Hospital | Lassen C.,Novartis | And 3 more authors.
European Respiratory Journal | Year: 2011

Two, once daily (q.d.) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease (COPD): the β 2-agonist indacaterol and the anticholinergic tiotropium. This blinded study compared the efficacy of these two agents and assessed their safety and tolerability. Patients with moderate-to-severe COPD were randomised to treatment with indacaterol 150 μg q.d. (n=797) or tiotropium 18 μg q.d. (n=801) for 12 weeks. After 12 weeks, the two treatments had similar overall effects on "trough" (24 h post-dose) forced expiratory volume in 1 s. Indacaterol-treated patients had greater improvements in transition dyspnoea index (TDI) total score (least squares means 2.01 versus 1.43; p<0.001) and St George's Respiratory Questionnaire (SGRQ) total score (least squares means 37.1 versus 39.2; p<0.001; raw mean change from baseline -5.1 versus -3.0), and were significantly more likely to achieve clinically relevant improvements in these end-points (indacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ, both p<0.001). Adverse events were recorded for 39.7% and 37.2% of patients in the indacaterol and tiotropium treatment groups, respectively. The most frequent adverse events were COPD worsening, cough and nasopharyngitis. Both bronchodilators demonstrated spirometric efficacy. The two treatments were well tolerated with similar adverse event profiles. Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes. Copyright©ERS 2011.

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