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BackgroundInterleukin (IL)-33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes.ObjectiveTo derive gene signatures from in vitro studies of IL-33-stimulated cells and use these to determine IL-33-associated enrichment patterns in asthma.MethodsSignatures downstream of IL-33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U-BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes.ResultsIL-33-activated gene signatures were cell-specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF-κB, IL-17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL-33-activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL-33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL-33 receptor, was up-regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co-receptor, was greatest in severe neutrophilic and mixed granulocytic asthma.ConclusionsIL-33-activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co-receptor expression. This suggests incorporating T2-low asthma in anti-IL-33 trials.

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases. Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti–IL-22 (fezakinumab [FZ]) is enriched in severe asthma. Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort. Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T H2, and T H17/T H22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P H22/IL-22 pathways. Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.

IntroductionReal-world trial data comparing single- with multiple-inhaler triple therapy (MITT) in COPD patients are currently lacking. The effectiveness of once-daily single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) and MITT were compared in usual clinical care.MethodsINTREPID was a multicentre, randomised, open-label, phase IV effectiveness study comparing FF/UMEC/VI 100/62.5/25 µg via the ELLIPTA inhaler with a clinician's choice of any approved non-ELLIPTA MITT in usual COPD clinical practice in five European countries. Primary end-point was proportion of COPD Assessment Test (CAT) responders (≥2-unit decrease in CAT score from baseline) at week 24. Secondary end-points in a subpopulation included change from baseline in forced expiratory volume in 1 s (FEV1) and percentage of patients making at least one critical error in inhalation technique at week 24. Safety was also assessed.Results3092 patients were included (FF/UMEC/VI n=1545; MITT n=1547). The proportion of CAT responders at week 24 was significantly greater with FF/UMEC/VI versus non-ELLIPTA MITT (OR 1.31, 95% CI 1.13–1.51; p1 was significantly greater with FF/UMEC/VI (77 mL versus 28 mL; treatment difference 50 mL, 95% CI 26–73 mL; pConclusionsIn a usual clinical care setting, treatment with once-daily single-inhaler FF/UMEC/VI resulted in significantly more patients gaining health status improvement and greater lung function improvement versus non-ELLIPTA MITT.

Background: The INTREPID study showed improved health status response and lung function in chronic obstructive pulmonary disease (COPD) usual care with single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) vs multiple-inhaler triple therapy (MITT; inhaled corticosteroid+long-acting muscarinic antagonist+long-acting β2-agonist [ICS+LAMA+LABA]). Aim: Evaluate INTREPID outcomes by prior medication strata. Methods: The open-label, phase IV INTREPID study included 3092 intent-to-treat (ITT) COPD patients who received non-ELLIPTA maintenance therapy for ≥16 weeks, had COPD Assessment Test (CAT) score ≥10 and ≥1 moderate/severe exacerbation in prior 3 years, randomised to FF/UMEC/VI 100/62.5/25µg via ELLIPTA or clinician choice of ICS+LAMA+LABA MITT in non-ELLIPTA devices for 24 weeks. Outcomes were analysed by prior medication strata (ICS+LAMA+LABA, ICS+LABA, LAMA+LABA). Results: Odds of CAT response and lung function improvement at Week 24 were statistically significantly greater for FF/UMEC/VI vs MITT in ICS+LAMA+LABA and ICS+LABA strata, and similar in LAMA+LABA stratum (Table). Adverse event incidence was broadly similar by prior medication strata. Conclusions: In usual care, FF/UMEC/VI significantly improved health status response and lung function vs MITT in patients on prior ICS-containing therapy. Method: GSK (206854/NCT03467425).

Background Randomized controlled trials (RCTs) conducted in the routine care setting provide the opportunity to better understand the effectiveness of new medicines but can present recruitment difficulties. An improved understanding of the challenges/opportunities for patient and healthcare professional (HCP) engagement in clinical research is needed to enhance participation and trial experience. In this study, we explored patient and HCP drivers for, and experiences of, participation in the Salford Lung Studies (SLS), and their views on future trial participation and the overall value of such trials. Methods This was a qualitative study set in Salford, UK, comprising patient telephone interviews (N = 10) and HCP advisory boards (one with general practitioners [GPs], one with practice managers [PMs]); all individuals had participated in the SLS. Semi-structured telephone interviews were recorded, transcribed and analysed thematically. Advisory board meetings were analysed based on transcriptions of audio recordings and field notes. Results For patients, key positive aspects of the SLS were the ease/convenience of study assessments and excellent relationships with study nurses. GPs and PMs considered the SLS to be well-organized and highlighted the value of research nurse support; they also described minor challenges relating to trial systems, initial financial strain on practices and staff turnover. All participants indicated that they were very likely to participate in future trials, citing a design closely aligned with routine care practice as essential. Several strategies to encourage trial participation were suggested, such as clearly communicating benefits to patients and ensuring flexible study assessments. Conclusions Patients and HCPs had positive experiences of the SLS. The study design, closely aligned with routine care, was considered important to their high likelihood of participating in future trials. The experiences of patients and HCPs in the SLS provide valuable insights that will help inform future best practice in the design and conduct of future real-world effectiveness RCTs in primary care. The detailed first-hand experiences of HCPs will be of significant value to others considering engaging in clinical research and participating in effectiveness RCTs.

Introduction Chez les patients BPCO, l’usage de plusieurs inhalateurs est lie a plus d’erreurs et a une moindre observance comparee aux inhalateurs uniques. Des donnees d’efficacite en vie reelle des TRT avec inhalateur unique vs multiples sur l’etat de sante dans la BPCO manquent. Nous avons evalue l’impact de la triple therapie inhalateur unique FF/UMEC/VI vs triples therapies inhalateurs multiples (TTIM ; associations CSI + LAMA + LABA) sur l’etat de sante, mesure par le COPD Assessment Test (CAT), sur 24 sem en soins cliniques (SC) habituels dans 5 pays EU. Methodes INTREPID est une etude d’efficacite de phase IV, randomisee, en ouvert, avec patients BPCO sous TRT de fond continu non-ELLIPTA (TTIM, ou bitherapie avec indication clinique documentee de passer a la triple therapie) pendant ≥ 16 sem avant randomisation, score CAT ≥ 10, et ≥ 1 exacerbation moderee/severe dans les 3 annees precedentes. Les patients ont ete randomises FF/UMEC/VI 100/62,5/25 μg via ELLIPTA (cohorte FF/UMEC/VI) ou choix de leur clinicien de toute association CSI + LAMA + LABA non-ELLIPTA (cohorte TTIM) pendant 24 sem. Seules 2 visites obligatoires pour reduire les interventions et refleter les SC habituels. Le critere d’evaluation principal etait la proportion de repondeurs CAT (diminution ≥ 2 unites score CAT par rapport a l’inclusion) a la S24. Les criteres d’evaluation secondaires etaient la variation par rapport a l’inclusion du VEMS et la proportion de patients avec ≥ 1 erreur critique dans la technique d’inhalation a la S24. La tolerance a ete evaluee de facon descriptive. Resultats La population ITT comptait 3092 patients (FF/UMEC/VI n = 1545 ; TTIM n = 1547). La probabilite d’etre repondeur au CAT a la S24 etait significativement plus elevee avec FF/UMEC/VI qu’avec TTIM (OR 1,31 ; p Tableau 1 ). A la S24, FF/UMEC/VI a ameliore le VEMS par rapport a l’inclusion, difference de 50 mL de plus que les TTIM (p Tableau 1 ). Au total, 38/653 patients traites par FF/UMEC/VI (6 %) et 7/230 patients traites par TTIM (3 %) ont fait ≥ 1 erreur critique dans la technique d’inhalation a la S24 (p = 0,103 ; Tableau 1). Les profils de tolerance etaient similaires entre cohortes, sans nouveaux signaux. Des EIGs de pneumonies sont survenus chez 26 (2 %) et 30 (2 %) patients des cohortes FF/UMEC/VI et TTIM. Conclusion En SC quotidiens, le TRT inhalateur unique FF/UMEC/VI compte un nombre significativement plus eleve de patients avec une amelioration de l’etat de sante et un meilleur benefice de la fonction pulmonaire, vs TTIM avec profils de tolerance similaires.

Introduction Ameliorer le controle de l’asthme est un objectif essentiel de la prise en charge de l’asthme. L’effet du mepolizumab sur le controle de l’asthme evalue par l’Asthma Control Questionnaire-5(ACQ-5) a ete rapporte dans les essais cliniques, mais les donnees en vraie vie sont limitees. Methodes REALITI-A, etude prospective en vraie vie, multicentrique, internationale, a enrole des patients avec un asthme severe a eosinophiles (ASE), ayant initie un traitement par mepolizumab sur 51 centres dans 7 pays. Une periode de 12 mois de donnees precedant l’inclusion etait necessaire pour decrire les donnees demographiques des participants, le fardeau de l’ASE et les traitements. Le controle de l’asthme a ete evalue par l’ACQ-5. Les scores a l’initiation ont ete compares aux scores a 3,6,9 et 12 mois. Les changements du controle depuis l’initiation et le taux de participants ayant une difference minimale importante [DMI] depuis l’initiation de 0,5 unites ont ete evalues. Des modeles mixtes de mesures repetees ont ete utilises pour l’analyse. Resultats Les donnees initiales etaient disponibles pour 368 patients qui ont complete un suivi de 12 mois ( Fig. 1 ). Dix-neuf pour cent (n = 70/368) des patients ont arrete le mepolizumab dans l’annee suivant l’initiation ; les raisons les plus frequentes etaient : la decision du patient (7 % ; n = 27/368), la discretion de l’investigateur (4 % ; n = 14/368), le manque d’efficacite (4 % ; n = 13/368). A l’inclusion, les patients avaient un score moyen ACQ-5 en moindres carres (IC95 %) de 2,99 (2,85 ; 3,13). L’initiation du mepolizumab a ete associee a une amelioration du controle de l’asthme, avec des moyennes MC (IC95 %) du score ACQ-5 a 3,6,9 et 12 mois de 1,81 (1,66 ; 1,96), 1,73 (1,56 ; 1,89), 1,84 (1,62 ; 2,05), et 1,84 (1,63 ; 2,05). Dans les 3 mois, 65 % (152/234) des patients ont obtenu une DMI, passant a 71 % (84/119) apres 12 mois. Les ameliorations ont ete observees dans chaque tranche de taux d’eosinophiles sanguins a l’inclusion, avec 56 % (10/18), 60 % (9/15), et 75 % (62/83) des patients avec des taux d’eosinophiles sanguins Conclusion Cette etude prospective en vie reelle confirme l’efficacite du mepolizumab chez les patients avec un ASE en termes d’amelioration du controle de l’asthme a 3 mois, avec des ameliorations significatives du score ACQ-5. Ces resultats montrent un benefice rapide et significatif du controle de l’asthme avec le mepolizumab en vraie vie, coherent avec les resultats des essais cliniques controles.

This paper addresses challenges of identifying, enrolling and retaining participants in a in a trial conducted within a routine care setting. All patients that are potential candidates for the treatments in routine clinical practice should be considered eligible for a pragmatic trial. To ensure generalizability, the recruited sample should have a similar distribution of the treatment effect modifiers as the target population. In practice this can be best achieved by including - within the selected sites - all patients without further selection. If relevant heterogeneity between subgroups is expected, increasing the relative proportion of the subgroup of patients in the heterogeneous trial could be considered (oversampling), or a separate trial in this subgroup can be planned. Selection will nevertheless occur. Low enrolment and loss to follow-up can introduce selection and can jeopardize validity as well as generalizability. Pragmatic trials are conducted in clinical practice rather than in a dedicated research setting, which could reduce recruitment rates. However, if a trial poses a minimal burden to the physician and the patient, and routine clinical practice is maximally adhered to, the participation rate may be high and loss to follow-up will not be a specific problem for pragmatic trials.

Nooreen Shaikh,1,2 Malcolm Johnson,3 David A Hall,4 Kian Fan Chung,1,2 John H Riley,3 Sally Worsley,5 Pankaj K Bhavsar1,2 1Experimental Studies, National Heart and Lung Institute, Imperial College London, 2Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, 3Respiratory Global Franchise, GlaxoSmithKline, Uxbridge, 4Fibrosis and Lung Injury Development Planning Unit, GlaxoSmithKline, Stevenage, 5Respiratory Research & Development, GlaxoSmithKline, Uxbridge, UK Background: Intracellular mechanisms of action of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a long-acting β2-adrenoceptor (β2R) agonist, were investigated in target cells: human airway smooth-muscle cells (ASMCs). Materials and methods: ASMCs from tracheas of healthy lung-transplant donors were treated with VI, UMEC, UMEC and VI combined, or control compounds (salmeterol, propranolol, ICI 118.551, or methacholine [MCh]). Cyclic adenosine monophosphate (cAMP) was measured using an enzyme-linked immunosorbent assay, intracellular free calcium ([Ca2+]i) using a fluorescence assay, and regulator of G-protein signaling 2 (RGS2) messenger RNA using real-time quantitative polymerase chain reaction. Results: VI and salmeterol (10–12–10–6 M) induced cAMP production from ASMCs in a concentration-dependent manner, which was greater for VI at all concentrations. β2R antagonism by propranolol or ICI 118.551 (10–12–10–4 M) resulted in concentration-dependent inhibition of VI-induced cAMP production, and ICI 118.551 was more potent. MCh (5×10–6 M, 30 minutes) attenuated VI-induced cAMP production (P

Effectiveness studies complement conventional randomised controlled trials by providing a holistic view of treatments in the setting of usual clinical practice. We present the protocol for the ongoing INTREPID (INvestigation of TRelegy Effectiveness: usual PractIce Design; ClinicalTrials.gov identifier: NCT03467425) study, a randomised, open-label, 24-week effectiveness study of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; Trelegy) delivered by the ELLIPTA inhaler versus non-ELLIPTA multiple-inhaler triple therapy in patients with chronic obstructive pulmonary disease (COPD) in usual practice settings. INTREPID was designed to provide evidence of FF/UMEC/VI effectiveness in patients with COPD managed in routine healthcare systems across multiple European countries. Between study initiation and end-of-study visits, patients will receive their medication and care as they would ordinarily receive it, from their usual healthcare provider at their usual healthcare centre. Study-specific intervention will be minimal. The primary end-point will be the proportion of COPD assessment test (CAT) responders, defined as a clinically meaningful improvement from baseline of ≥2 units, at week 24. The CAT was chosen as it provides health status information relevant to patients, physicians, health technology agencies and payers. Lung function (forced expiratory volume in 1 s) and critical inhaler errors will also be assessed in a subgroup of patients. The strengths and weaknesses of the protocol and some of the challenges associated with conducting this multicountry study, such as differences in healthcare systems and treatment practices across sites, will also be discussed., The INTREPID COPD study is investigating the real-world effectiveness of fluticasone furoate/umeclidinium/vilanterol delivered by ELLIPTA versus multiple-inhaler triple therapies in Europe. This article presents the protocol and discusses effectiveness studies in COPD. http://bit.ly/2ZzBAo3

Background: Mepolizumab (mepo) is an approved add-on treatment for adults with severe refractory eosinophilic asthma (SEA). Objective: To describe the real-world population of patients (pts) with SEA receiving mepo. Methods: REALITI-A is a prospective, observational, multi-country cohort study using integrated data capture methods (eCRFs, claims data, phone app). Study aims to recruit ~1,050pts with asthma, prescribed mepo 100mg SC in a clinical practice setting. Reimbursement criteria vary by country and often include the following: blood eosinophil counts (BEC; ≥150 [baseline] and/or ≥300 [prior yr] cells/µL) and 2–4 exacerbations [prior yr] or maintenance oral corticosteroid (mOCS) use. Primary objective: to compare clinically significant exacerbations (CSE; requiring OCS and/or ED visit/hospitalisation) pre-/post-mepo use. Baseline characteristics from eCRF of the initial pts are shown here. Results: By 30 Sept 2017, 170pts were enrolled (Table). Of the 137pts with a BEC, 89.8% had counts ≥150 cells/µL at baseline (Geo mean [SD log]: 436 (1.2) cells/µL) and ≥75% had ≥300 cells/µL (prior yr). In total, 85.2% and 56.1% of pts had ≥2 and ≥4 CSE in the prior yr, respectively, and 56.1% of pts had mOCS use. Conclusions: The real-world vs clinical trial population of pts with SEA receiving mepo have more frequent exacerbations in the past yr and higher BEC. This might be driven by reimbursement criteria. Funding: GSK [204710]

BACKGROUND: Umeclidinium (UMEC; long-acting muscarinic antagonist [LAMA])/vilanterol (VI; long-acting beta2-agonist [LABA]) and fluticasone propionate/salmeterol (FP/SAL) (inhaled corticosteroid/LABA) are approved maintenance therapies for chronic obstructive pulmonary disease (COPD). Two studies compared efficacy and safety of UMEC/VI with FP/SAL in patients with moderate-to-severe COPD with no exacerbations in the previous year. METHODS: In these 12-week, multicenter, double-blind, parallel-group, double-dummy trials, randomized (1:1) patients received once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 250/50 mcg (DB2114930 n = 353 and 353; DB2114951 n = 349 and 348, respectively; intent-to-treat). Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, dyspnea, quality of life (QoL) and safety. RESULTS: UMEC/VI demonstrated statistically significant, clinically meaningful improvements in lung function measures versus FP/SAL. For 0-24 h wmFEV1 (Day 84), improvements with UMEC/VI versus FP/SAL were 74 mL (95% confidence interval [CI]: 38-110; DB2114930) and 101 mL (63-139; DB2114951) (both p 1 unit) and QoL (St George's Respiratory Questionnaire Total score >4-unit decrease) in both studies with no statistical differences between treatments. Adverse event rates were similar: 26 and 30% UMEC/VI; 27 and 31% FP/SAL. CONCLUSIONS: Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in statistically significant, clinically meaningful improvements in lung function versus twice-daily FP/SAL 250/50 mcg in patients with moderate-to-severe COPD with infrequent exacerbations. Both treatments improved dyspnea and QoL. CLINICAL TRIAL REGISTRATION: DB2114930/NCT01817764; DB2114951/NCT01879410.

Lymphocyte numbers are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. Phosphatidylinositol-3-kinase delta (PI3Kδ) is involved in lymphocyte activation. We investigated the effect of PI3Kδ inhibition on cytokine release from COPD lymphocytes. We also evaluated phosphorylated ribosomal S6 protein (rS6) as a potential biomarker of PI3Kδ activation. Peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells isolated from healthy never smokers (HNS), smokers (S) and COPD patients were stimulated to induce a T cell receptor response. The effects of a PI3Kδ specific inhibitor (GSK045) on cytokine release and rS6 phosphorylation were measured by Luminex and flow cytometry respectively. The effects of GSK045 on cytokine production from PHA stimulated chopped lung samples were investigated. GSK045 reduced cytokine release from PBMCs, BAL cells and chopped lung. Inhibition was greatest in the chopped lung model, with approximately 80% inhibition of IFNγ, IL-2, IL-17 and IL-10. PI3Kδ inhibition suppressed rS6 phosphorylation in unstimulated airway T-lymphocytes by up to 60%. Inhibition of PI3Kδ suppressed T cell cytokine production in COPD patients. rS6 phosphorylation shows potential as a biomarker to assess PI3Kδ activity. This article is protected by copyright. All rights reserved.

Peter Kardos,1 Sally Worsley,2 Dave Singh,3 Miguel Román-Rodríguez,4 David E Newby,5 Hana Müllerová2 1Group Practice and Respiratory, Allergy and Sleep Unit, Red Cross Maingau Hospital, Frankfurt, Germany; 2GSK, Stockley Park, Middlesex, 3University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK; 4Primary Care Respiratory Research Unit, Instituto de Investigación Sanitaria de Palma IdisPa, Palma de Mallorca, Spain; 5BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh, UK Abstract: Long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design. Keywords: real-world observational study, cardiovascular, cerebrovascular, safety, umeclidinium, vilanterol

Asthma and chronic obstructive pulmonary disease (COPD) are characterized in their pathogenesis by chronic inflammation in the airways. Phosphoinositide 3-kinase δ (PI3Kδ), a lipid kinase expressed predominantly in leukocytes, is thought to hold much promise as a therapeutic target for such inflammatory conditions. Of particular interest for the treatment of severe respiratory disease is the observation that inhibition of PI3Kδ may restore steroid effectiveness under conditions of oxidative stress. PI3Kδ inhibition may also prevent recruitment of inflammatory cells, including T lymphocytes and neutrophils, as well as the release of proinflammatory mediators, such as cytokines, chemokines, reactive oxygen species, and proteolytic enzymes. In addition, targeting the PI3Kδ pathway could reduce the incidence of pathogen-induced exacerbations by improving macrophage-mediated bacterial clearance. In this review, we discuss the potential and highlight the unknowns of targeting PI3Kδ for the treatment of respiratory disease, focusing on recent developments in the role of the PI3Kδ pathway in inflammatory cell types believed to be critical to the pathogenesis of COPD.

This second article in the series on pragmatic trials describes the challenges in selection of sites for pragmatic clinical trials and the impact on validity, precision, and generalizability of the results. The selection of sites is an important factor for the successful execution of a pragmatic trial and impacts the extent to which the results are applicable to future patients in clinical practice. The first step is to define usual care and understand the heterogeneity of sites, patient demographics, disease prevalence and country choice. Next, specific site characteristics are important to consider such as interest in the objectives of the trial, the level of research experience, availability of resources, and the expected number of eligible patients. It can be advisable to support the sites with implementing the trial-related activities and minimize the additional burden that the research imposes on routine clinical practice. Health care providers should be involved in an early phase of protocol development to generate engagement and ensure an appropriate selection of sites with patients who are representative of the future drug users.

Asthma and chronic obstructive pulmonary disease (COPD) are characterized in their pathogenesis by chronic inflammation in the airways. Phosphoinositide 3-kinase δ (PI3Kδ), a lipid kinase expressed predominantly in leukocytes, is thought to hold much promise as a therapeutic target for such inflammatory conditions. Of particular interest for the treatment of severe respiratory disease is the observation that inhibition of PI3Kδ may restore steroid effectiveness under conditions of oxidative stress. PI3Kδ inhibition may also prevent recruitment of inflammatory cells, including T lymphocytes and neutrophils, as well as the release of proinflammatory mediators, such as cytokines, chemokines, reactive oxygen species, and proteolytic enzymes. In addition, targeting the PI3Kδ pathway could reduce the incidence of pathogen-induced exacerbations by improving macrophage-mediated bacterial clearance. In this review, we discuss the potential and highlight the unknowns of targeting PI3Kδ for the treatment of respiratory disease, focusing on recent developments in the role of the PI3Kδ pathway in inflammatory cell types believed to be critical to the pathogenesis of COPD.