Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma?

SummaryRationaleLittle is known about the use of biomarkers in guiding treatment decisions in routine asthma management. The objective of this study was to determine whether adding a LABA to an ICS would control bronchial hyperresponsiveness (BHR) at an overall lower dose of ICS when titration of medication was based upon the assessment of routine clinical measures with or without the measurement of BHR.MethodsAfter a 2-week run-in period, subjects (⩾12 years) were randomized to one of three treatment groups. Two groups followed a BHR treatment strategy (based on clinical parameters [lung function, asthma symptoms, and bronchodilator use] and BHR) and were treated with either fluticasone propionate/salmeterol (FSCBHR group) or fluticasone propionate (FPBHR group) (n=156 each). The third group followed a clinical treatment algorithm (based on clinical parameters alone) and were treated with fluticasone propionate (FPREF group; n=154). All treatments were administered via Diskus®. Treatment doses were adjusted as needed every 8 weeks for 40 weeks according to the subject's derived severity class, which was based on clinical measures of asthma control with or without BHR.ResultsThe mean total daily inhaled corticosteroids (ICS) dose during the double-blind treatment period was lower, although not statistically significant, in the FSCBHR group compared with the FPBHR group (a difference of −42.9mcg; p=0.07). Compared with the FPREF group, the mean total daily ICS dose was higher in the FSCBHR group (a difference of 85.2mcg) and was significantly higher in the FPBHR group (a difference of 131.2mcg, p=0.037).ConclusionThis study demonstrated that for most subjects, control of BHR was maintained when treatment was directed toward control of clinical parameters. In addition, there was a trend towards control of BHR and clinical measures at a lower dose of ICS when used concurrently with salmeterol

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD:the value of inhaled corticosteroids

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm(3). METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV(1)] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV(1) were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting β(2)-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component’s contribution in patients with moderate-to-severe COPD. Trial registration: ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-021-01772-2

The Long-term Burden of COPD Exacerbations during Maintenance Therapy and Lung Function Decline

Data Sharing Statement The dataset supporting the conclusions of this article was derived from the Clinical Practice Research Datalink (www.cprd.com) and the Optimum Patient Care Research Database (www.opcrd.co.uk). The CPRD has broad National Research Ethics Service Committee (NRES) ethics approval for purely observational research using the primary care data and established data linkages. The OPCRD has ethical approval from the National Health Service (NHS) Research Authority to hold and process anonymized research data (Research Ethics Committee reference: 15/EM/0150). This study was approved by the Anonymized Data Ethics Protocols and Transparency (ADEPT) committee – the independent scientific advisory committee for the OPCRD, and the Independent Scientific Advisory Committee (ISAC) for the CPRD. The authors do not have permission to give public access to the study dataset; researchers may request access to CPRD or OPCRD data for their own purposes. Access to CPRD can be made via the CPRD website (https://www.cprd.com/researcher/) or via the inquiries email [email protected]. Access to OCPRD can be made via the OCPRD website (https://opcrd.co.uk/our-database/data-requests/) or via the inquiries email [email protected]. Funding This study is funded by AstraZeneca. AstraZeneca participated in the study design and reporting.Peer reviewedPublisher PD

Association between COPD exacerbations and lung function decline during maintenance therapy

Acknowledgements: Writing and editorial support was provided by Dr Julia Granerod, supported by the Observational and Pragmatic Research Institute Pte. Ltd (OPRI). Funding: This study was funded by AstraZeneca.Data availability statement: Data may be obtained from a third party and are not publicly available. The dataset supporting the conclusions of this article was derived from the Clinical Practice Research Datalink (www.cprd.com) and the Optimum Patient Care Research Database (www.opcrd.co.uk). The CPRD has broad National Research Ethics Service Committee (NRES) ethics approval for purely observational research using the primary care data and established data linkages. The OPCRD has ethical approval from the National Health Service (NHS) Research Authority to hold and process anonymised research data (Research Ethics Committee reference: 5/EM/0150). This study was approved by the Anonymised Data Ethics Protocols and Transparency (ADEPT) committee – the independent scientific advisory committee for the OPCRD, and the Independent Scientific Advisory Committee (ISAC) for the CPRD. The authors do not have permission to give public access to the study dataset; researchers may request access to CPRD or OPCRD data for their own purposes. Access to CPRD can be made via the CPRD website (https://www.cprd.com/researcher/) or via the enquiries email enquiries@cprd. com. Access to OCPRD can be made via the OCPRD website(https://opcrd.co.uk/our-database/data-requests/) or via the enquiries email [email protected]. The study was designed, implemented, and registered in accordance with the criteria of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS19879).Peer reviewedPublisher PD

Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD

Inhaled corticosteroid/long-acting β2-agonist combination therapy is a recommended treatment option for patients with chronic obstructive pulmonary disease (COPD) and increased exacerbation risk, particularly those with elevated blood eosinophil levels. SOPHOS (NCT02727660) evaluated the efficacy and safety of two doses of budesonide/formoterol fumarate dihydrate metered dose inhaler (BFF MDI) versus formoterol fumarate dihydrate (FF) MDI, each delivered using co-suspension delivery technology, in patients with moderate-to-very severe COPD and a history of exacerbations. In this phase 3, randomised, double-blind, parallel-group, 12-52-week, variable length study, patients received twice-daily BFF MDI 320/10 µg or 160/10 µg, or FF MDI 10 µg. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 12. Secondary and other endpoints included assessments of moderate/severe COPD exacerbations and safety. The primary analysis (modified intent-to-treat) population included 1843 patients (BFF MDI 320/10 µg, n=619; BFF MDI 160/10 µg, n=617; and FF MDI, n=607). BFF MDI 320/10 µg and 160/10 µg improved morning pre-dose trough FEV1 at week 12 versus FF MDI (least squares mean differences 34 mL [p=0.0081] and 32 mL [p=0.0134], respectively), increased time to first exacerbation (hazard ratios 0.827 [p=0.0441] and 0.803 [p=0.0198], respectively) and reduced exacerbation rate (rate ratios 0.67 [p=0.0001] and 0.71 [p=0.0010], respectively). Lung function and exacerbation benefits were driven by patients with blood eosinophil counts ≥150 cells·mm-3. The incidence of adverse events was similar, and pneumonia rates were low (≤2.4%) across treatments. SOPHOS demonstrated the efficacy and tolerability of BFF MDI 320/10 µg and 160/10 µg in patients with moderate-to-very severe COPD at increased risk of exacerbations

Physiological predictors of peak inspiRatory flow using Observed lung function results (POROS) : evaluation at discharge among patients hospitalized for a COPD exacerbation

This study was supported by AstraZeneca. The abstract of this paper was presented at the American Thoracic Society International Conference 2017 as a poster presentation with interim findings.Peer reviewedPublisher PD

Cost-Effectiveness of Asthma Step-Up Therapy as an Increased Dose of Extrafine-Particle Inhaled Corticosteroid or Add-On Long-Acting Beta2-Agonist

The analyses were funded by an unrestricted grant from Teva Pharmaceuticals Limited of Petach Tikva, Israel. Access to data from the Optimum Patient Care Research Database was co-funded by Research in Real-Life Ltd (RiRL), Cambridge, UK. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. The authors thank Julie von Ziegenweidt for assistance with data extraction.Peer reviewedPublisher PD

CONQUEST Quality Standards : For the Collaboration on Quality Improvement Initiative for Achieving Excellence in Standards of COPD Care

Acknowledgments We thank Dr Seyi Soremekun, Jonathan Marshall, Jennie Medin and Irena Brookes-Smith for their valuable contributions to the design of the study. We would also like to acknowledge Ms Andrea Teh Xin Yi (BSc, Hons) of the Observational and Pragmatic Research Institute (OPRI), Singapore, for editorial and formatting assistance which supported the development of this publication. Professor Dave Singh is supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC). Funding CONQUEST is conducted by Optimum Patient Care Global and Observational and Pragmatic Research Institute and is co-funded by Optimum Patient Care Global and AstraZenecaPeer reviewedPublisher PD

EGF-induced bronchial epithelial cells drive neutrophil chemotactic and anti-apoptotic activity in asthma

Chronic damage and repair of the bronchial epithelium are features of asthma. We have previously reported that ex vivo stimulation of normal bronchial epithelial cells with epidermal growth factor (EGF), a key factor of epithelial repair, enhances the mechanisms of neutrophil accumulation, thereby promoting neutrophil defences during acute injury but potentially enhancing inflammation in chronic airway diseases. We have now sought to (i) determine whether this EGF-dependent pro-neutrophil activity is increased in asthma, where EGF and its epithelial receptor are over-expressed, and (ii) elucidate some of the mechanisms underlying this asthmatic epithelial-neutrophil interaction. Primary bronchial epithelial cells (PBEC) from healthy subjects, mild asthmatics and moderate-to-severe asthmatics (Mod/Sev) were stimulated with EGF, a model that mimics a repairing epithelium. Conditioned culture media (EGF-CM) were assessed for neutrophil chemotactic and anti-apoptotic activities and inflammatory mediator production. EGF induced the epithelium to produce soluble mediators with neutrophil chemotactic (p&lt;0.001) and pro-survival (p?=?0.021) activities which were related to the clinical severity of asthma (trend p?=?0.010 and p?=?0.009, respectively). This was associated with enhanced IL-6, IL-8, GM-CSF and TNF-? release, and cytokine-neutralising experiments using EGF-CM from Mod/Sev asthmatics demonstrated a role for GM-CSF in neutrophil survival (p&lt;0.001). Pre-treatment of neutrophils with specific inhibitors of the myeloid-restricted class I phosphatidylinositol-3-OH kinase (PI(3)K) isoforms showed that the EGF-CM from Mod/Sev asthmatics depended on the ? (p&lt;0.021) but not ? isoforms, while neutrophil survival required multiple class I PI(3)Ks. The EGF-induced chemotactic, but not pro-survival activity, involved RhoA signaling in neutrophils (p?=?0.012). EGF whose activity is upregulated in asthma induces ex vivo the epithelium from asthmatic patients to produce pro-neutrophil activities; these are related to asthma severity and, in moderate-to-severe asthmatics, involves class IB PI(3)K? signaling, providing a potential therapeutic target for neutrophilic forms of asthma

Cost-Effectiveness Comparison of Salmeterol/Fluticasone Propionate versus Montelukast in the Treatment of Adults with Persistent Asthma

Objective: To compare the relative cost effectiveness of salmeterol (50mug)/ fluticasone propionate (100mug) with that of oral montelukast (10mg) as initial maintenance therapy in patients with persistent asthma uncontrolled on short-acting beta2-agonist therapy alone. Study design: A cost-effectiveness analysis was performed based on effectiveness and resource utilisation data that was prospectively collected from a randomised, double-blind, double-dummy, 12-week trial. Patients and methods: Patients (>15 years of age) who had asthma for at least 6 months. Effectiveness measurements in this analysis included improvement in forced expiratory volume in 1 second (FEV1) and symptom-free days (SFDs). Cost of asthma drug treatment as well as costs related to an asthma exacerbation were used in the cost analysis. The study assumed a payer's perspective. All costs are in 2001 US dollars. Results: Of the 423 patients eligible for the study, 211 were randomised to salmeterol/fluticasone propionate and 212 to montelukast. Treatment with salmeterol/fluticasone propionate resulted in a significantly higher proportion of patients who achieved a 12% increase in FEV1 (successful treatment) [salmeterol/fluticasone propionate: 71% vs montelukast: 39%; pAsthma, Beta 2 adrenoceptor agonists, Cost effectiveness, Leukotriene D4 antagonists, Montelukast, Pharmacoeconomics, Salmeterol/fluticasone propionate