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IntroductionAlthough most asthma is mild to moderate, severe asthma accounts for disproportionate personal and societal costs. Poor co-ordination of care between primary care and specialist settings is recognised as a barrier to achieving optimal outcomes. The Primary Care Severe Asthma Registry and Education (PCSAR-EDU) project aims to address these gaps through the interdisciplinary development and evaluation of both a ‘real-world’ severe asthma registry and an educational programme for primary care providers. This manuscript describes phase 1 of PCSAR-EDU which involves establishing interdisciplinary consensus on criteria for the: (1) definition of severe asthma; (2) generation of a severe asthma registry and (3) definition of an electronic-medical record data-based Clinician Behaviour Index (CBI).Methods and analysisIn phase 1, a modified e-Delphi activity will be conducted. Delphi panellists (n≥13) will be invited to complete a 30 min online survey on three separate occasions (i.e., three separate e-Delphi ‘rounds’) over a 3-month period. Expert opinion will be collected via an open-ended survey (‘Open’ round 1) and 5-point Likert scale and ranking surveys (‘Closed’ round 2 and 3). A fourth and final Delphi round will occur via synchronous meeting, whereby panellists approve a finalised ideal ‘core criteria list’, CBI and corresponding item weighting.Ethics and disseminationEthical approval has been obtained for the activities involved in phase 1 from the University of Toronto’s Human Research Ethics Programme (approval number 39695). Future ethics approvals will depend on information gathered in the proceeding phase; thus, ethical approval for phase 2 and 3 of this study will be sought sequentially. Findings will be disseminated through conference presentations, peer-reviewed publications and knowledge translation tools.

Resume Objectif Faciliter la distinction entre l’asthme et la maladie pulmonaire obstructive chronique (MPOC) en pratique de premiere ligne de tous les jours, et fournir des strategies therapeutiques pratiques a l’aide de cas de spirometrie pour illustrer comment reconnaitre le chevauchement clinique et spirometrique entre l’asthme et la MPOC. Sources d’information Les approches decrites ici s’appuient sur les lignes directrices factuelles et sur l’expertise des auteurs, y compris des observations de recherches menees par les auteurs dans les domaines de l’asthme, de la prise en charge de la MPOC et des examens de spirometrie en premiere ligne. Message principal Certains patients presentent des caracteristiques cliniques communes a l’asthme et a la MPOC. Ces deux maladies sont associees a un certain degre d’inflammation des voies respiratoires, mediee par l’expression accrue de proteines inflammatoires. Il existe toutefois des differences evidentes entre l’asthme et la MPOC pour ce qui est de l’inflammation presente dans les poumons. La confusion diagnostique entre la MPOC et l’asthme survient le plus souvent chez les patients âges qui se plaignent de symptomes respiratoires, surtout en contexte de tabagisme ou d’exposition professionnelle. Les diagnostics cliniques d’asthme et de MPOC sont fondes sur les antecedents du patient, les symptomes, l’examen physique et les mesures objectives de la fonction respiratoire. La spirometrie apres bronchodilatation est toujours necessaire pour confirmer un nouveau diagnostic de MPOC et elle doit egalement etre realisee avant la bronchodilatation pour poser un diagnostic d’asthme. Dans de nombreux cas, toutefois, il n’est pas evident d’interpreter les resultats de la spirometrie. Conclusion Il est essentiel de bien comprendre la nature et la portee du chevauchement spirometrique entre l’asthme et la MPOC afin de concevoir une strategie therapeutique qui s’appuie sur des facteurs qui incluent les antecedents medicaux et familiaux, les signes et les symptomes, et l’interpretation claire des donnees de spirometrie. Cette information sera utilisee differemment aupres de chaque patient pour arriver au bon diagnostic clinique et selectionner le traitement le plus approprie.

Objective To facilitate distinction between asthma and chronic obstructive pulmonary disease (COPD) in day-to-day primary care practice, and provide practical treatment strategies using spirometric cases to outline how to recognize the clinical and spirometric overlap between asthma and COPD. Sources of information The approaches described here were developed using evidence-based guidelines and the expertise of the authors, including research findings by the authors in the areas of asthma, COPD management, and spirometric testing in primary care. Main message There are patients with clinical or spirometric features of both asthma and COPD. Both asthma and COPD are associated with some degree of inflammation of the respiratory tract, mediated by the increased expression of inflammatory proteins. However, there are clear differences between asthma and COPD in the pattern of inflammation that occurs in the lungs. Diagnostic confusion between COPD and asthma is most likely to arise in older patients with respiratory complaints, particularly against a background that includes cigarette smoke or workplace exposure. Both asthma and COPD are clinical diagnoses based on patient history, symptoms, physical examination findings, and objective measures of lung function. Postbronchodilator spirometry is always needed to confirm a new diagnosis of COPD and should also be performed prebronchodilator for the diagnosis of asthma. However, in many cases, the interpretation of spirometry results is not straightforward. Conclusion Understanding the nature and extent of the spirometric overlap between asthma and COPD is critical for tailoring a therapeutic strategy that is based on factors that include medical and family history, signs and symptoms, and a clear interpretation of spirometry data. This information will be leveraged differently for individual patients to arrive at the correct clinical diagnosis and to select the most appropriate therapy.

During the clinical development of a fixed-dose combination of drugs, it is best practice to conduct dose-finding studies to determine the optimal dose of each component. The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose–response relationship of olodaterol in combination with tiotropium 5 μg, and compare it with the dose response of olodaterol monotherapy. In this double-blind, parallel-group trial, patients were randomized to receive either tiotropium 5 μg or a fixed-dose combination of tiotropium 5 μg with olodaterol 2 μg, 5 μg, or 10 μg, delivered once daily via the Respimat® for 4 weeks (NCT00696020). Patients had a diagnosis of chronic obstructive pulmonary disease and post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥ 30 and

COPD causes considerable health and economic burden worldwide, with incidence of the disease expected to continue to rise. Inhaled bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), are central to the maintenance treatment of patients with COPD. Clinical studies have demonstrated that combined LAMA + LABA therapies improve efficacy while retaining a safety profile similar to LAMA or LABA alone. This has led to the development of several LAMA/LABA fixed-dose combination (FDC) therapies, which provide patients with the convenience of two active compounds in a single inhaler. GFF MDI (Bevespi Aerosphere®) is an FDC of glycopyrrolate/formoterol fumarate 18/9.6 µg formulated using innovative co-suspension delivery technology for administration via metered dose inhaler (MDI). GFF MDI was developed to make a treatment option available for patients who have a requirement or preference to use an MDI, rather than a dry powder or soft mist inhaler. Now that several LAMA/LABA FDCs have been approved for use in COPD, we review the impact of dual-bronchodilator treatment on COPD therapy and discuss recent clinical studies that are helping to develop a more comprehensive understanding of how LAMA/LABA FDCs can improve patient outcomes.

Introduction Combining long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat® inhaler. Methods This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks. Results Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments. Conclusions Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased. Funding Boehringer Ingelheim. Trial registration: ClinicalTrials.gov number, NCT01040403. Electronic supplementary material The online version of this article (doi:10.1007/s12325-015-0239-8) contains supplementary material, which is available to authorized users.

This analysis provides a comprehensive clinical assessment of the long-term safety of the licensed dose of olodaterol (5 µg once daily [QD] via Respimat® inhaler) in patients with chronic obstructive pulmonary disease by exploring the occurrence of acknowledged side effects of long-acting β2-agonists as well as those included in the olodaterol and formoterol labels. We analysed pooled data from two replicate, double-blind studies of olodaterol (5 µg QD via Respimat®) compared to formoterol (12 µg twice daily [BID]) or placebo over 48 weeks (1222.13, NCT00793624; 1222.14, NCT00796653). Patients could continue their background treatment. The analysis considered adverse events (AEs) typically associated with β2-agonists, including cardiovascular events, as well as administration-related events. Descriptive statistics were provided for the incidence of AEs and aggregated AEs. The analysis included 1379 patients: 460 placebo, 459 olodaterol and 460 formoterol; AEs were reported by 70.9, 71.7 and 69.1% of patients, respectively. Exposure-adjusted incidence rates of cardiac AEs (arrhythmia and myocardial ischaemia) and cough were numerically lower in the olodaterol group than the formoterol group, while nasopharyngitis, throat irritation, metabolism and psychiatric disorders were numerically higher in the olodaterol group. The most frequent event in the olodaterol group was nasopharyngitis (placebo 8.0%; olodaterol 12.9%; formoterol 10.0%). Except for cough (incidence rate ratio of 0.46 [95% confidence interval 0.24, 0.89] in favour of olodaterol), there were no significant differences between active groups. In conclusion, olodaterol 5 µg QD was well tolerated over 48 weeks with a typical β2-agonist safety profile comparable to formoterol 12 µg BID., Chronic lung disease: Drug safety confirmed The long-term safety of a recently-certified inhaled drug for the treatment of chronic lung disease is verified by scientists in Germany. The management of chronic obstructive pulmonary disease involves inhaled drugs called long-acting β2 agonists (LABAs). The most recently-certified LABA is called olodaterol. Andrea Koch at the Klinikum der Ludwig-Maximilians-Universität in Munich, Germany, and co-workers have clarified the long-term safety of olodaterol during two trials that compared it with formoterol, an existing LABA. The trials lasted 48 weeks and involved 1379 patients—460 were given a placebo, 459 received 5 µg olodaterol via a Respimat device, and 460 received formoterol. Side effects from olodaterol were no more severe or persistent than those associated with formoterol. Reassuringly, the new drug also displayed similar or slightly lower incidence of cardiovascular side effects such as heart palpitations compared with formoterol.

The global prevalence of chronic obstructive pulmonary disease (COPD) is rising, although the disease is often underdiagnosed or misdiagnosed as asthma. Early diagnosis and intervention in the primary care setting may improve outcomes and reduce the overall burden of COPD and its comorbidities. Bronchodilators are the mainstay of pharmacologic treatment in international and national guidelines, with long-acting agents administered alone or as part of a combination regimen in patients who are persistently symptomatic and/or at high risk of COPD exacerbations. Here, we report results of a systematic literature search to review the evidence supporting several approved bronchodilator monotherapies, as well as dual bronchodilator treatment, combination therapy with inhaled corticosteroids plus one or two bronchodilators and other emerging COPD treatment options.

The objective of this study was to assess the cost effectiveness of the dual bronchodilator indacaterol/glycopyrronium (IND/GLY) compared with salmeterol/fluticasone combination (SFC) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who had a history of one or no exacerbations in the previous year, in Canada, France, Italy, and Portugal. A patient-level simulation was developed to compare the costs and outcomes of IND/GLY versus SFC based on data from the LANTERN trial (NCT01709903). Monte-Carlo simulation methods were employed to follow individual patients over various time horizons. Population and efficacy inputs were derived from the LANTERN trial. Considering the payers’ perspective, only direct costs were included. Costs and health outcomes were discounted annually at 3.0 % for all countries. Unit costs were taken from publically available sources with all costs converted to euros (€). The cost base year was 2015. Deterministic and probabilistic sensitivity analyses were undertaken to test the robustness of the model results. IND/GLY was found to be the dominant (more effective and less costly) treatment option compared with SFC in all four countries. The use of IND/GLY was associated with mean total cost savings per patient over a lifetime of €6202, €1974, €1611, and €220 in Canada, France, Italy, and Portugal, respectively. Sensitivity analysis showed that exacerbation rates had the largest impact on incremental costs and quality-adjusted life-years (QALYs). The probability of IND/GLY being cost effective was estimated to be >95 % for thresholds above €5000/QALY. In patients with moderate to severe COPD, IND/GLY is likely to be a cost-effective treatment alternative compared with SFC.

Dave Singh,1 M Reza Maleki-Yazdi,2 Lee Tombs,3 Ahmar Iqbal,4 William A Fahy,5 Ian Naya5 1Medicines Evaluation Unit, University of Manchester, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK; 2Division of Respiratory Medicine, Women’s College Hospital, University of Toronto, ON, Canada; 3Precise Approach LTD, London UK; 4Respiratory Medical Franchise, GSK, Research Triangle Park, NC, USA; 5Respiratory Medicines Development Centre, GSK, Stockley Park, Middlesex, UK Background: Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy. Methods: This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25µg with UMEC 62.5µg, VI 25µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25µg with tiotropium (TIO) 18µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100mL in trough forced expiratory volume in 1second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation. Results: In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P

This pilot study aimed to identify early stages of chronic obstructive pulmonary disease (COPD) in an urban population of smokers and ex-smokers using the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2001, 2003) classification guidelines and to assess the impact of early disease on quality of life. Smokers and ex-smokers of >or= 10 pack years and age >or= 50 years were recruited. After an initial telephone interview, eligible subjects completed a clinical assessment, spirometry tests, and the St. George's Respiratory Questionnaire (SGRQ). A total of 244 subjects completed the study; 91 subjects (37%) were normal, 153 subjects (63%) met the criteria for GOLD stages 0 to III: 65 stage 0 (27%), 43 stage I (18%), 38 stage II (16%), 7 stage III (3%) and 0 in stage IV. The stage 0 patients were younger than any other COPD groups (p

Background: Bronchodilator therapy with long-acting muscarinic antagonists (LAMAs), β 2 -agonists (LABAs) and inhaled corticosteroids (ICS) is commonly used to improve outcomes in COPD. We examined clinically important deteriorations (CID) to quantify response to ICS/LABA+LAMA or LAMA/LABA. Methods: Two post hoc pooled analyses were performed on data from four 12-wk studies of umeclidinium 62.5mcg (UMEC)+ICS/LABA vs placebo (PBO)+ICS/LABA, and three 24-wk studies of umeclidinium/vilanterol 62.5/25mcg (UMEC/VI) vs tiotropium 18mcg (TIO). The analyses examined if dual bronchodilation ±ICS delayed onset of CID vs ICS/LABA or LAMA. CID was defined as: decrease from baseline ≥100mL in trough FEV 1 , decline in health-related quality of life (≥4 units St George9s Respiratory Questionnaire total score), or moderate/severe COPD exacerbation; CID was sustained if lasting ≥2 visits or 50% of time thereafter. Results: In the 12-wk studies, 377/819 (46%) UMEC+ICS/LABA and 554/818 (68%) PBO+ICS/LABA patients had ≥1 CID (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.45–0.59; p Conclusion: CID is a useful endpoint to differentiate responses to treatment with dual and mono bronchodilator therapy ±ICS in COPD. Funded by GSK (NCT: 01957163, 02119286, 01772134, 01772147, 01316900, 01316913, 01777334).

Background: To investigate efficacy of umeclidinium/vilanterol (UMEC/VI) in preventing clinically important deterioration (CID) in intent-to-treat (ITT) and maintenance-naive (MN) populations with COPD. Methods: Post hoc analysis of four 24-week, parallel-group, blinded trials comparing UMEC/VI 62.5/25mcg vs tiotropium (TIO) 18mcg (3 trials) or placebo (PBO; 1 trial). The main outcome was percentage of patients with ≥1 CID (composite endpoint: decrease from baseline trough forced expiratory volume in 1 second [FEV 1 ; ≥100mL] and/or increase from baseline in St George9s Respiratory Questionnaire total score[≥4 units]and/or a moderate/severe COPD exacerbation). Results: Least squares means difference in trough FEV 1 at 24 weeks with UMEC/VI vs TIO was 95mL in the ITT and 146mL in the MN population (both p 1 was 167mL in the ITT and 156mL in the MN population (both p Conclusion: Dual therapy with UMEC/VI reduced the risk of CID in COPD vs TIO or PBO in both ITT and MN populations. Funded by GSK. NCT/GSK study: 01316900/113360; 01316913/113374; 01777334/117115, 01313650/113373.

SummaryBackgroundOlodaterol is a novel long-acting β2-agonist (LABA) with ≥24-h duration of action in preclinical and clinical studies.ObjectiveThis Phase II, multicentre, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study evaluated four doses of once-daily olodaterol over 4 weeks in patients with chronic obstructive pulmonary disease (COPD), based on efficacy, safety and pharmacokinetic parameters.MethodsPatients received olodaterol inhalation solution or placebo via Respimat® Soft Mist™ inhaler once daily for 4 weeks. Pulmonary function testing was performed pre-dose (trough) and up to 3 or 6 h post-dose, depending on visit. Primary end point was change from baseline in trough forced expiratory volume in 1 s (FEV1) after 4 weeks' treatment. Secondary end points included change from baseline in peak FEV1 and FEV1 area under the curve from 0 to 6 h.Results405 patients with COPD were randomised and assigned to treatment. Mean baseline post-bronchodilator FEV1 was 1.50 L (54% predicted). All olodaterol doses provided statistically significant increases in trough FEV1 compared to placebo (2 μg: 0.061 L [p = 0.0233]; 5 μg: 0.097 L [p = 0.0003]; 10 μg: 0.123 L [p

INTRODUCTION: No recent Canadian studies with physician- and spirometry-confirmed diagnosis of chronic obstructive pulmonary disease (COPD) that assessed the burden of COPD have been published.OBJECTIVE: To assess the costs associated with maintenance therapy and treatment for acute exacerbations of COPD (AECOPD) over a one-year period.METHODS: Respirologists, internists and family practitioners from across Canada enrolled patients with an established diagnosis of moderate to severe COPD (Global initiative for chonic Obstructive Lung Disease stages 2 and 3) confirmed by postbronchodilator spirometry. Patient information and health care resources related to COPD maintenance and physician-documented AECOPD over the previous year were obtained by chart review and patient survey.RESULTS: A total of 285 patients (59.3% male; mean age 70.4 years; mean pack years smoked 45.6; mean duration of COPD 8.2 years; mean postbronchodilator forced expiratory volume in 1 s 58.0% predicted) were enrolled at 23 sites across Canada. The average annual COPD-related cost per patient was $4,147. Across all 285 patients, maintenance costs were $2,475 per patient, of which medications accounted for 71%. AECOPD treatment costs were $1,673 per patient, of which hospitalizations accounted for 82%. Ninety-eight patients (34%) experienced a total of 157 AECOPD. Treatment of these AECOPD included medications and outpatient care, 19 emergency room visits and 40 hospitalizations (mean length of stay 8.9 days). The mean cost per AECOPD was $3,036.DISCUSSION: The current costs associated with moderate and severe COPD are considerable and will increase in the future. Appropriate use of medications and strategies to prevent hospitalizations for AECOPD may reduce COPD-related costs because these were the major cost drivers.

Asthmatic patients hyperventilate during acute attacks, but controversy persists as to whether they breathe rapidly, deeply or both. We monitored respiratory rate under the three following conditions: (1) asthma treated in the emergency room; (2) airways obstruction provoked by methacholine inhalation; and (3) airways obstruction provoked by exercise. In 47 acutely ill asthmatic patients, respiratory rate was higher than in 42 nonasthmatic control patients in the emergency room. Pretreatment respiratory rate correlated with peak expiratory flow rate and forced expired volume in one second. In 17 asthmatic patients and 16 healthy volunteers, breathing pattern was monitored by respiratory inductance plethysmography. Methacholine inhalation and exercise provoked significant airways obstruction in asthmatic patients but not in control subjects. In asthmatic patients, minute ventilation and tidal volume increased above that of control subjects following methacholine and exercise, but the rate was no higher than in control subjects. We conclude that the respiratory rate is increased in naturally occurring asthma, but not when acute airways obstruction is induced transiently in the laboratory. In the former setting, the respiratory rate is correlated with spirometric measures of airflow obstruction, but the weakness of the correlation does not allow the respiratory rate to be used as a substitute for spirometry. (Chest 1990; 97:58-62)

Introduction Dual bronchodilator therapy is reserved as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) and provides benefits in lung function and health status versus monotherapy. The aim of this study was to determine whether early initiation of a dual bronchodilator versus monotherapy reduced the risk of deterioration in COPD. Methods This post hoc pooled analysis investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg/day compared with tiotropium (TIO) 18 mcg/day in a maintenance-naïve (MN) subgroup of patients relative to the intent-to-treat (ITT) population from three 6-month active comparator studies (n = 1747). Other treatment arms (UMEC/VI 125/25, VI 25 and UMEC 125) comprised 850 patients in total but were not included in this analysis. The primary endpoint was trough forced expiratory volume in 1 s (FEV1). St George’s Respiratory Questionnaire (SGRQ) score, rescue medication use, and a novel composite endpoint of short-term clinically important deterioration (CID; ≥100 ml decrease in trough FEV1, ≥4-unit increase in SGRQ score, or a COPD exacerbation) were also assessed. Results UMEC/VI improved trough FEV1 versus TIO at day 169 [least squares mean (95% confidence interval): MN: 146 ml (102–189) and ITT: 95 ml (71–118); both P