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Aim.The purpose was to provide the rationale of test in regard to uniformity of fine particles dose for pressurised metered dose inhalers (pMDIs). Materials and methods.The pMDIs containing suspensions of salbutamol sulfate (SS) or solutions of beclometasone dipropionate (BD) were studied by laser diffraction and high performance liquid chromatography (HPLC). The particle size distribution of SS, the average dose mass and uniformity of dose mass, the average delivered dose and the uniformity of delivered dose, the average fine particles dose and uniformity of fine particles dose were determined. Apparatus A was used for assessment of fine particles dose. Results.The two analytical procedures for the quantitative determination of SS and BD by HPLC were validated in the ranges with low concentrations of these substances. The 5 medicinal products in pMDI dosage form were studied: 3 preparations were with SS and 2 ones contained BD. It was shown that three products with SS were very similar in regard to particle size distribution in containers and the average values of delivered dose were almost the same, but these products were different in the average dose mass and fine particle dose. According to the research results, the expediency of determining the average dose mass and the tests concerning uniformity of dosing of preparations by dose mass and by fine particle dose was substantiated. It was shown that in the case of pMDI the dosing of solutions of BD was more uniform compared to suspensions of SS. The approaches of leading and other pharmacopoeias concerning uniformity of dosing for pMDIs were critically discussed. The expediency of determination of uniformity of fine particle dose at the stage of pharmaceutical development was substantiated, as the therapeutic effect depends on fine particle dose. Issues concerning standardization pMDIs in regard to uniformity of fine particle dose were discussed. Conclusions.The expediency of standardization and quality control of pMDIs in regard to such attributes as the average dose mass, which characterizes the volume of the metering chamber of the valve as well as the uniformity of the dose mass and the uniformity of fine particle dose, which assure the therapeutic effect of each dose of the product was substantiated

Luca Richeldi,1 Alessio Piraino,2 Francesco Macagno,1 Gianluigi Micarelli,2 Eleonora Ingrassia2 1Unità Operativa Complessa di Pneumologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico A, Gemelli, Rome; 2Chiesi Italia S.p.a., Parma, ItalyCorrespondence: Gianluigi MicarelliChiesi Italia S.p.a., Via Giacomo Chiesi 1, Parma 43122, ItalyTel +39 345 6350692Fax +39 0521 279592Email g.micarelli@chiesi.comBackground: The fixed triple combination Beclometasone dipropionate/Formoterol fumarate/Glycopyrronium (BDP/FF/G, Trimbow®), an extrafine formulation in a unique pressurized metered dose inhaler, is indicated for the maintenance treatment in adult patients with moderate to severe COPD, not adequately treated by ICS/LABA or LABA/LAMA. Besides the evidence from three randomized controlled trials, the impact of fixed triple therapy has not been extensively evaluated in a real-world population of COPD patients. TRITRIAL (TRIple Therapy in Real life: Impact on Adherence and HeaLth status) is a non-interventional study to assess the effect of BDP/FF/G in a real world setting in Italy.Design: TRITRIAL is a 12-month, multicenter, cohort, prospective, longitudinal observational study. Two follow-up visits will be performed at 6 and 12 months, respectively. The study includes the collection of anamnestic clinical and functional data before the start of BDP/FF/G. The study is built for digital conduction, from signature of the informed consent on a dedicated web platform, to the collection of questionnaires and clinical data on the eCRF.Population: A total of 800 patients with COPD ranging from Global Initiative for Obstructive Lung Disease (GOLD) stages 2 to 4, receiving therapy with BDP/FF/G according to the Summary of Product Characteristics and local clinical practice, will be recruited. All concomitant therapies will be permitted for the duration of the study.Evaluations: The primary endpoint is the change of CAT score at 12 months versus baseline. Secondary endpoints are adherence, health-related quality of life, sleep quality, disease-related outcomes (lung function and COPD exacerbations), device usability, economic resources consumption, and safety.Conclusion: TRITRIAL study is expected to give relevant information about effectiveness of BDP/FF/G fixed triple therapy in a real-life setting of patients with COPD, where adherence, usability of inhalers and patient’s preference of the device are crucial factors for the success of the therapy.Keywords: COPD, symptoms, health status, adherence, LAMA, LABA, ICS

Background The effects of triple therapy on gas trapping in COPD are not fully understood. We evaluated the effects of the long acting bronchodilator components of the extrafine single inhaler triple therapy beclometasone dipropionate/formoterol/glycopyrronium (BDP/F/G) pMDI on gas trapping. Methods This open-label, randomised, single centre, 2-way cross-over study recruited 23 COPD patients taking inhaled corticosteroid combination treatments and with residual volume (RV) > 120% predicted at screening. Inhaled BDP was taken during run-in and washout periods. Baseline lung function (spirometry, lung volumes, oscillometry) was measured over 12 h prior to randomisation to BDP/F/G or BDP/F for 5 days followed by washout and crossover. Lung function was measured prior to dosing on day 1 and for 12 h post-dose on day 5. Results Co-primary endpoint analysis: BDP/F/G had a greater effect than BDP/F on FEV1 area under the curve over 12 h (AUC0–12) (mean difference 104 mls, p = 0.0071) and RV AUC0–12 (mean difference − 163 mls, p = 0.0028). Oscillometry measurements showed a greater effect of BDP/F/G on the difference between resistance at 5 and 20 Hz (R5–R20) AUC0–12, which measures small airway resistance (mean difference − 0.045 kPa/L/s, p = 0.0002). Comparison of BDP/F with the baseline measurements (BDP alone) showed that F increased FEV1 AUC0–12 (mean difference 227 mls) and improved RV AUC0–12 (mean difference − 558 mls) and R5–R20 AUC0–12 (mean difference − 0.117 kPa/L/s), all p Conclusions In COPD patients with hyperinflation, the G and F components of extrafine BDP/F/G improved FEV1, RV and small airway function. These long acting bronchodilators target small airway function, thereby improving gas trapping and airflow. Trial registration The study was retrospectively registered at ClinicalTrials.gov on 15th February 2019 (No.: NCT03842904, https://clinicaltrials.gov/ct2/show/NCT03842904).

Introduction Asthma is associated with significant economic burden. Inhaled corticosteroid and long-acting beta2-agonist (ICS/LABA) combination therapies are considered mainstays of treatment. We describe real-world use of ICS/LABAs by comparing treatment persistence and adherence among patients with asthma in the United Kingdom initiating fluticasone furoate/vilanterol (FF/VI) versus budesonide/formoterol (BUD/FM) or beclometasone dipropionate/formoterol (BDP/FM). Methods A retrospective new-user active comparator database study was conducted in the IQVIA Medical Research Database. Propensity score (PS) matching was performed for FF/VI versus BUD/FM, and FF/VI versus BDP/FM. The primary objective was to compare patient treatment persistence (time to discontinuation), while secondary objectives included assessing adherence (mean proportion of days covered [PDC] with medication in the study period) and the proportions of patients achieving ≥ 50% and ≥ 80% PDC. Results New users of FF/VI (N = 966), BUD/FM (N = 5931) and BDP/FM (N = 9607) were identified and PS-matched: FF/VI (n = 945) versus BUD/FM (n = 3272), and FF/VI (n = 902) versus BDP/FM (n = 3465). At 12 months, treatment persistence was 69% (FF/VI), 53% (BUD/FM) and 57% (BDP/FM). The likelihood of treatment discontinuation within 12 months after initiation with FF/VI was 35% lower than with BUD/FM and 31% lower than for BDP/FM (both p

What you need to know A 35 year old man with a prior diagnosis of mild asthma presents to his general practitioner with a three month history of intermittently waking at night with cough and shortness of breath. He works as a chef and has found it difficult to complete a full shift during this time. He has been prescribed beclometasone 200 μg twice a day for a long time and asks if there is a need to change his treatment in light of his new persistent symptoms. Poorly controlled or moderate asthma occurs when patients experience either daily symptoms of asthma, nocturnal awakenings, more than two exacerbations per year, or some limitation of their daily activities.12 With frequent alterations of guidelines, and continual development of new medications and delivery devices, choosing a suitable treatment strategy can pose a challenge in clinical practice. In this article, we present the latest guidance on drugs used in primary care for poorly controlled asthma in adults. ### ICS/LABA combination Inhaled corticosteroids (ICS, eg, beclometasone dipropionate, budesonide, fluticasone furoate, etc) and long acting β agonists (LABA, eg, formoterol, salmeterol, vilanterol, etc) are the mainstay of treatment for poorly controlled or moderate asthma (table 1). ICS suppress airway inflammation leading to reduced bronchial hyperresponsiveness. LABAs act on …

Iki šiol nebuvo atlikta tyrimų, vertinusių trijų vaistų derinio viename inhaliatoriuje veiksmingumą gydant sergančiuosius astma. Šiame straipsnyje pristatomi du nauji klinikiniai tyrimai, kurie pirmą kartą įvertino itin smulkių dalelių beklometazono dipropionato (BDP), formaterolio fumarato (FF) ir glikopironio (G) derinio viename inhaliatoriuje veiksmingumą, lyginant su BDP ir FF deriniu, gydant sergančiuosius nekontroliuojama astma. Tyrimų rezultatai parodė, kad sergantiesiems nekontroliuojama astma ir gydomiems įkvepiamaisiais gliukokortikoidais bei ilgo veikimo β2 agonistais, pridėjus ilgo veikimo muskarino antagonistą, pagėrėja plaučių funkcija bei sumažėjo paūmėjimų dažnis.

Introduction: Incorrect inhaler technique is one reason why the efficacies of inhaled asthma treatments in clinical trials and effectiveness in the real world differ. Inhaler technique is critical for drug delivery to the lungs; incorrect technique negatively impacts asthma control and long-term outcomes. Breath-triggered inhalers (BTIs) can simplify drug administration and are suitable for most patients, including those with reduced inspiratory flow. Until recently, no inhaled corticosteroid/long-acting β2-agonist combination BTI was available in Europe. The flutiform® (fluticasone propionate/formoterol fumarate [FP/FORM]) k-haler® is the first combination BTI now approved in Europe for asthma maintenance treatment.Areas covered: We review studies examining the challenges posed to patients by different inhaler types and explore evidence demonstrating the clinical efficacy of FP/FORM administered via a pressurized metered-dose inhaler. We also review the pharmacokinetic/pharmacodynamic studies supporting FP/FORM k-haler use, and consider data showing high lung deposition with the device. Finally, we review patient experiences using the BTI, device characteristics, and health economic aspects.Expert opinion: Despite the availability of therapies, asthma control levels remain low, and there is a clear need for easy-to-use inhalers. Research to increase our understanding of critical errors with each inhaler and how to overcome them is important for improving care.Abbreviations: AUCt: area under the plasma concentration-time curve from the time of dosing to the last measurable concentration; BDP: beclometasone dipropionate; BTI: breath-triggered inhaler; BUD: budesonide; CI: confidence interval; Cmax: maximum observed plasma concentration; DPI: dry powder inhaler; FDC: fixed-dose combination; FEV1: forced expiratory volume in 1 s; FORM: formoterol fumarate; FP: fluticasone propionate; HCP: health-care professional; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; OR: odds ratio; PIL: patient information leaflet; pMDI: pressurized metered-dose inhaler; SAL: salmeterol xinafoate.

Background Current pharmacological therapies for COPD improve quality of life and symptoms and reduce exacerbations. Given the progressive nature of COPD, it is arguably more important to understand whether the available therapies are able to delay clinical deterioration; the concept of "clinically important deterioration" (CID) has therefore been developed. We evaluated the efficacy of the single-inhaler triple combination beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G), using data from three large 1-year studies. Methods The studies compared BDP/FF/G to BDP/FF (TRILOGY), tiotropium (TRINITY), and indacaterol/glycopyrronium (IND/GLY; TRIBUTE). All studies recruited patients with symptomatic COPD, FEV1

Background A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. Methods TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint. Results Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p p Conclusions In patients with COPD, FEV1 Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html).

A new pediatric fixed combination of beclometasone dipropionate (BDP) 50 μg and formoterol fumarate (FF) 6 μg via pressurized metered-dose inhaler (pMDI) (CHF1535, Chiesi, Italy) was investigated. In a double-blind, randomized, placebo-controlled, cross-over study, a single CHF1535 administration using AeroChamber Plus™ spacer device (2 actuations, total dose BDP 100 μg/FF 12 μg) was compared to the same pMDI free combination in 56 asthmatic children aged ≥ 5 and < 12 years. Primary efficacy variable was forced expiratory volume during the first second (FEV1) area under the curve corrected by time over 12 h following morning dose (AUC0-12h). Further CHF1535 doses (50 μg/6 μg, 100 μg/12 μg, and 200 μg/24 μg) were also explored. Adverse events, electrocardiogram, and vital signs were monitored for safety. CHF1535 was non-inferior to free combination [adjusted mean difference (95% CI) 0.004 L (- 0.050, 0.041] with lower confidence limit greater than the limit set at 0.1 L. FEV1 AUC0-12h of each CHF1535 dose vs placebo were 0.037 L (p = 0.160), 0.119 L (p < 0.001), and 0.094 (p < 0.001) for 50/6, 100/12, and 200/24, respectively. No safety signals were found.Conclusion: CHF1535 was as effective as free combination BDP/FF, with a trend towards a dose-related response. All treatments were safe.Trial registration: ClinicalTrials.gov ID: NCT01584492 What is Known: •Inhaled pressurized metered-dose solutions (pMDI) are the preferred treatment for pediatric asthma. •Combination therapy of inhaled corticosteroids and long-acting β2- agonists is a well-established approach to control airway inflammation and airway obstruction also in pediatric patients. What is New: •A novel pediatric pMDI fixed combination of beclomethasone dipropionate 50 μg and formoterol fumarate 6 μg (CHF 1535) was non-inferior to the free combination at the same dose in pulmonary function over the 12-h post-dose period in asthmatic children, with trend towards a dose-related response.

Jaco Voorham,1,2 Simonetta Baldi,3 Luigi Santoro,4 Marjan Kerkhof,1,5 Marco Contoli,6 Leonardo M Fabbri,6 Huib AM Kerstjens,7 Jose Luis López-Campos,8 Nicolas Roche,9 Dave Singh,10 Claus F Vogelmeier,11 David B Price1,12 1Observational & Pragmatic Research Institute Pte Ltd, Singapore, Singapore; 2Data to Insights Research Solutions, Lisbon, Portugal; 3Department of Global Clinical Development, Chiesi SAS, Bois Colombes Cedex, France; 4Department of Global Clinical Development, Chiesi Farmaceutici S.p.A, Parma, Italy; 5Mescio Research, Blauwestad, The Netherlands; 6Section of Respiratory Medicine, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 7Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; 8Respiratory Diseases Unit, University Hospital Virgen Del Rocío, Seville, Spain; 9Service de Pneumologie, Hôpital Cochin, APHP, Centre-Université de Paris, Paris, France; 10University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B PriceAcademic Primary Care, Division of Applied Health Sciences University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD 198785, UKTel +65 6962 3627Email dprice@opri.sgPurpose: This study aimed to evaluate the non-inferiority of initiating extrafine beclometasone dipropionate/formoterol fumarate (BDP/FF) versus double bronchodilation (long-acting beta-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) among patients with a history of chronic obstructive pulmonary disease (COPD) exacerbations.Patients and Methods: A historical cohort study was conducted using data from the UK’s Optimum Patient Care Research Database. Patients with COPD ≥ 40 years at diagnosis were included if they initiated extrafine BDP/FF or any LABA/LAMA double therapy as a step-up from no maintenance therapy or monotherapy with inhaled corticosteroids (ICS), LAMA, or LABA and a history of ≥ 2 moderate/severe exacerbations in the previous two years. The primary outcome was exacerbation rate from therapy initiation until a relevant therapy change or end of follow-up. Secondary outcomes included rate of acute respiratory events, acute oral corticosteroids (OCS) courses, and antibiotic prescriptions with lower respiratory indication, modified Medical Research Council score (mMRC) ≥ 2, and time to first pneumonia diagnosis. The non-inferiority boundary was set at a relative difference of 15% on the ratio scale. Five potential treatment effect modifiers were investigated.Results: A total of 1735 patients initiated extrafine BDP/FF and 2450 patients initiated LABA/LAMA. The mean age was 70 years, 51% were male, 41% current smokers, and 85% had FEV1 < 80% predicted. Extrafine BDP/FF showed non-inferiority to LABA/LAMA for rate of exacerbations (incidence rate ratio [IRR] = 1.01 [95% CI 0.94– 1.09]), acute respiratory events (IRR = 0.98 [0.92– 1.04]), acute OCS courses (IRR = 1.01 [0.91– 1.11]), and antibiotic prescriptions (IRR = 0.99 [0.90– 1.09]), but not for mMRC (OR = 0.93 [0.69– 1.27]) or risk of pneumonia (HR = 0.50 [0.14– 1.73]). None of the a priori defined effect modifier candidates affected the comparative effectiveness.Conclusion: This study found that stepping up to extrafine BDP/FF from no maintenance or monotherapy was not inferior to stepping up to double bronchodilation therapy in patients with a history of exacerbations.Keywords: real-world, electronic health records, observational, comparative effectiveness, heterogeneity, chronic obstructive pulmonary disease

Purpose The aim of this study was to develop and compare proliposome powder and proliposome tablet formulations for drug delivery from a Pari-LC Sprint nebulizer. Methods Proliposome powders were prepared by the slurry method and sorbitol or mannitol carbohydrate carrier were used in a 1:10 and 1:15 w/w lipid phase to carrier ratio. Beclometasone dipropionate (BDP; 2 mol%) was incorporated in the lipid phase. Proliposome powders were compressed into tablets, and liposomes were generated from proliposome powders or tablets within the nebulizer reservoir for subsequent aerosolization. Results Comparatively, shorter sputtering times were reported for the tablet formulations (≈ Conclusion Overall, this study showed that proliposome tablets could be disintegrated within a Pari-LC Sprint nebulizer to generate inhalable aerosol, with high drug output and hence can be manufactured on large scale to overcome the storage problems associated with powder formulations.

BACKGROUND: Budesonide has been proven to be an effective treatment for microscopic colitis (MC). However, the two current commercially available preparations are released in the ileum. Beclomethasone dipropionate (Clipper®) is a synthetic corticosteroid with topical colonic release. OBJECTIVE: This study aimed to explore whether an open-label treatment with beclomethasone dipropionate is an effective treatment for MC. METHODS: Prospectively collected data of 30 patients from six centres were retrospectively analysed. All patients had a confirmed diagnosis of idiopathic MC (lymphocytic and collagenous colitis) and were symptomatic (i.e. ≥ 21 loose stools over a seven-day period). Treatment consisted of 10 mg beclomethasone daily for four weeks, followed by 5 mg daily for another four weeks. The primary end point was the proportion of patients in remission (i.e. a mean of

Background: The goal of asthma treatment, outlined by GINA experts, is to achieve and maintain full control of the disease. One critical risk factor for poor asthma control is exposure to tobacco smoke. The purpose of this analysis isto assess the effectiveness and safety of long-term therapy with an extrafine combined aerosol formulation of beclometasone dipropionate and formoterol (BDP/F) in asthmatics for current and ex-smokers vs non-smokers. Methods: The CASPER study was an observational, noninterventional, prospective, multicentre trial. Asthmatics currently being managed long-term with BDP/F pressurized metred-dose inhaler (pMDI) were divided based on smoking status into three groups: current smokers, ex-smokers, and non-smokers. The subjects were evaluated at 0, 3, and 6 months for symptom intensity, asthma control, frequency of exacerbations and dose of inhaled corticosteroids. Adverse drug reactions were also monitored. Results: Out of 16,844 patients, 2833 (16.8%) were ex-smokers and 3312 (19.7%) were current smokers. At the beginning of the observation, the current smokers were the most symptomatic subgroup of patients with the greatest limitation on life activity. During long-term treatment with extrafine BDP/F-pMDI , diurnal and nocturnal asthma symptoms, rescue medication use, and limitations of activity secondary to asthma were markedly decreased in all subgroups, with a statistically significant effect in smokers and ex-smokers, albeit at the end of the observation, a higher percentage of symptomatic patients remained in the groups of current smokers and ex-smokers while a lower percentage of symptomatic patients was observed among the non smokers. At the 6-month follow-up, an improvement in asthma control compared to baseline, according to GINA criteria, was reported in 77.1% of current smokers, 75.2% of exsmokers, and 75% of non-smokers, but full asthma control was more frequently achieved in non smokers (64.0% fulfilled GINA criteria of asthma control) compared to current smokers and ex-smokers (54.9% and 51.5%, respectively). A total of 525 nonserious ADRs were reported in 422 patients (3.2%), all of which were within expectations. Conclusions: Combination therapy with extrafine BDP/F-pMDI is an effective therapy across a broad spectrum of asthmatics, irrespective of smoking status,albeit the overall asthma control is worse in those with a smoking history.

Background A number of single-inhaler triple therapies are being developed for asthma, including the extrafine formulation of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G). Given asthma is a heterogenous disease, we investigated whether the clinical response to the addition of the long-acting muscarinic antagonist component within inhaled triple therapy was impacted by a range of clinical characteristics. Methods These were pre-specified and post-hoc sub-group analyses of TRIMARAN and TRIGGER, which were double-blind, 52-week studies comparing medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with the respective BDP/FF strengths in adults with uncontrolled asthma and a history of ≥ 1 exacerbation. Co-primary endpoints were pre-dose forced expiratory volume in 1 s (FEV1) at Week 26 and the rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints: peak FEV1 at Week 26 and average morning peak expiratory flow over the first 26 weeks in each study, and severe exacerbation rate over 52 weeks (pooled data). Results Baseline clinical characteristics (pre-specified analyses) had no consistent effect on the lung function improvements with BDP/FF/G. For the exacerbation endpoints, sub-groups with higher reversibility gained greatest relative benefit from BDP/FF/G versus BDP/FF. In post-hoc analyses with patients sub-grouped by screening blood eosinophil values, in TRIMARAN the greatest relative effect of BDP/FF/G versus BDP/FF on the lung function endpoints was in the ≤ 300 cells/µL group; in TRIGGER, eosinophil levels did not markedly influence the relative efficacy of BDP/FF/G versus BDP/FF. Eosinophil levels did not influence relative efficacy on moderate-to-severe or severe exacerbations. Conclusion Overall, the relative efficacy of extrafine BDP/FF/G versus BDP/FF was not influenced by a range of clinical characteristics. However, some patient sub-groups gained additional benefit from BDP/FF/G for certain endpoints. In particular, for exacerbations the relative efficacy of BDP/FF/G was greater in more reversible patients. Trial registration ClinicalTrials.gov: TRIMARAN, NCT02676076 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676076?term=NCT02676076&draw=2&rank=1,); TRIGGER, NCT02676089 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676089?term=NCT02676089&draw=2&rank=1)

Recently, two "fixed triple" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting beta(2)-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of "fixed triple" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form "open triple" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.

Background: This study evaluated the lung deposition and the distribution pattern in the airways of a fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) (100/6 μg) delivered as an extrafine dry powder formulation (mass median aerodynamic diameter, MMAD (μm) BDP = 1.5; FF = 1.4) through the NEXThaler® device in healthy subjects, asthmatics, and patients with COPD. Methods: Healthy subjects (n = 10), asthmatic patients (n = 9; 30%≤FEV1 < 80%), and COPD patients (n = 9; FEV1/FVC ≤70%, 30%≤FEV1 < 50%) completed this open-label, single administration (inhalation of four actuations) parallel group study. After inhalation of 99mTc-radiolabeled BDP/FF combination (radiolabeled BDP + unlabeled FF), the drug deposition was assessed using a gamma-scintigraphy technique. Patients' lung function was assessed. Results: No significant difference in drug deposition was observed between the three study groups. Mean lung deposition, extrathoracic deposition, and amount exhaled ranged, respectively, between 54.9% and 56.2%, between 41.8% and 43.2%, and between 1.6% and 3.3% of BDP emitted dose (71.7 ± 2.5 μg) for the three study groups. The central to peripheral ratio (reflecting the lung distribution pattern) ranged between 1.23 and 2.02 for the three study groups, indicating a distribution of the drug throughout the airways, including periphery. The study treatment produced a forced expiratory volume in one second (FEV1) increase over time, reaching a maximum improvement generally within 1–4 hours. Conclusions: The fixed extrafine dry powder combination BDP/FF (100/6 μg) administered through the DPI NEXThaler® achieved similar intrapulmonary deposition in healthy subjects, in asthmatic patients, and COPD patients (approximately 55% of emitted dose) irrespective of the underlying lung disease with a negligible amount of exhaled particles. The study showed high reliability of the device, reproducible dosing, and distribution throughout the lungs. The results supported the concept of efficient delivery of the combination to the target pulmonary regions, thanks to the extrafine formulation. FEV1 profile confirmed a relevant pharmacodynamic effect of the product.

Brian Lipworth, Chris RuiWen Kuo, Sunny Jabbal Division of Molecular & Clinical Medicine, Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK Abstract: A single inhaler containing inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA)/long-acting muscarinic antagonist (LAMA) is a more convenient way of delivering triple therapy in patients with COPD. Single triple therapy has been shown to be superior at reducing exacerbations and improving quality of life compared to LABA/LAMA, especially in patients with a prior history of frequent exacerbations and blood eosinophilia, who have ICS responsive disease. The corollary is that patients with infrequent exacerbations who are noneosinophilic may be safely de-escalated from triple therapy to LABA/LAMA without loss of control. Pointedly, there is a substantially increased risk of pneumonia associated with the triple therapy containing fluticasone furoate but not beclometasone dipropionate or budesonide. Since triple therapy is also better than ICS/LABA at reducing exacerbations and improving lung function, symptoms, and quality of life, this brings into question the rationale for using ICS/LABA. Hence, we propose a simplified pragmatic decision process based on symptoms, prior to exacerbation history, and blood eosinophils to select which patients should be given a single triple inhaler or LABA/LAMA. Differences in patient preference of inhaler device, formulations and drugs will also determine which triple inhaler prescribers elect to use. Keywords: COPD, inhaled corticosteroid, long-acting beta-agonist, long-acting muscarinic antagonist, lung function, exacerbation

Lack of coordination between the beginning of the inhalation and device triggering is one of the most frequent errors reported in connection with the use of pMDI devices. Earlier results suggested a significant loss in lung deposition as a consequence of late actuation. However, most of our knowledge on the effect of poor synchronization is based on earlier works on CFC devices emitting large particles with high initial velocities. The aim of this study was to apply numerical techniques to analyse the effect of late device actuation on the lung dose of a HFA pMDI drug emitting high fraction of extrafine particles used in current asthma and COPD therapy. A computational fluid and particle dynamics model was combined with stochastic whole lung model to quantify the amount of drug depositing in the extrathoracic airways and in the lungs. High speed camera measurements were also performed to characterize the emitted spray plume. Our results have shown that for the studied pMDI drug late actuation leads to reasonable loss in terms of lung dose, unless it happens in the second half of the inhalation period. Device actuation at the middle of the inhalation caused less than 25% lung dose reduction relative to the value characterizing perfect coordination, if the inhalation time was between 2 and 5 s and inhalation flow rate between 30 and 150 L/min. This dose loss is lower than the previously known values of CFC devices and further support the practice of triggering the device shortly after the beginning of the inhalation instead of forcing a perfect synchronization and risking mishandling and poor drug deposition.

Background: Smoking is as prevalent in asthmatics as in the general population. Asthmatic smokers benefit less from inhaled corticosteroids (ICS) than non-smoking asthmatics, possibly due to more smoking-induced small airways disease. Thus targeting small airways may be important in treating asthmatic (ex-) smokers. We hypothesized that extrafine particle ICS improve small airways function more than non-extrafine particle ICS in asthmatic (ex-) smokers. Methods: We performed an open-label, randomized, three-way cross-over study comparing extrafine beclomethasone (HFA-QVAR) to non-extrafine beclomethasone (HFA-Clenil) and fluticasone (HFA-Flixotide) in 22 smokers and 21 ex-smokers with asthma (>= 5 packyears).Results: Improvement from baseline in PD20 adenosine after using QVAR, Clenil or Flixotide was 1.04 +/- 1.71, 1.09 +/- 2.12 and 0.94 +/- 1.97 doubling doses, mean +/- standard deviation (SD), respectively. The change from baseline in R-5-R-20 at PD20 adenosine after using QVAR, Clenil or Flixotide was -0.02 +/- 0.27, 0.02 +/- 0.21, and -0.02 +/- 0.31 kPa sL(-1), mean +/- SD, respectively. The change in PD20 adenosine and R5R20 at PD20 adenosine were neither statistically significant different between QVAR and Clenil (p = 0.86 and p = 0.82) nor between QVAR and Flixotide (p = 0.50 and p = 0.96).Conclusion: Similar effectiveness in improving small airways function was found for extrafine and non-extrafine particle ICS treatment for asthmatic smokers and ex-smokers. (C) 2017 Elsevier Ltd. All rights reserved.

Therapeutic pulmonary surfactants are currently investigated in clinical medicine as corticosteroids delivery vehicles into the lung. The influence of the corticosteroids Budesonide and Beclometasone dipropionate on the surface properties of aqueous solutions of the therapeutic surfactant preparation Curosurf ® has been studied using the black foam film and the wetting film methods. The measurements of probability W for black foam film formation versus surfactant concentration C indicated that the two characteristics of black foam film stability – critical concentration C c and threshold concentration C t – for Curosurf ® mixtures with 3 μg/cm 3 corticosteroids practically coincide with the values for Curosurf ® alone. The disjoining pressure/black film thickness isotherms for mixtures of Curosurf ® + corticosteroids are slightly shifted to larger film thicknesses compared to isotherm of Curosurf ® alone. The measurements of wetting film thickness and wetting contact angles showed that the hydrophobization of SiO 2 -solid surface by mixtures of Curosurf ® + corticosteroids is slightly smaller than the hydrophobization due to Curosurf ® only. Budesonide and Beclometasone dipropionate equally influence the wetting behaviour of the Curosurf ® solutions. These results indicate that the addition of corticosteroids does not alter significantly the surface properties of the therapeutic pulmonary surfactant.

INTRODUCTION: An extrafine combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo.METHODS: Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40-75 years; moderate to severe COPD (post-bronchodilator FEV1 40-80% predicted, FEV1/FVC PRIMARY OBJECTIVE: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR0-4h) at each dose level. Secondary variables included: HR0-12h, HR peak and individual timepoint; QTcF interval; SBP and DBP AUC0-12h; and potassium and glucose AUC0-4h. Adverse events (AEs) were collected.RESULTS: Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (-0.2 bpm [95% CI -1.3, 0.9] for 200/12 μg and 0.6 bpm [-0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo.CONCLUSIONS: Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.

Introduction and objectives A retrospective cohort analysis was conducted comparing persistence with, and adherence to, different inhaled corticosteroid/long-acting-β2-agonist (ICS/LABA) treatments by asthma patients. Here we report findings from patients initiating treatment with either FF/VI or BDP/FM, the latter administered either as flexible or fixed-dose. Methods Patients in the UK with data registered in The Health Improvement Network (THIN) database, who had a first prescription (index date) for any ICS/LABA between 1 January 2013–17 January 2018 (study period) and a prior asthma diagnosis, were included if they had ≥12 months medical history prior to index date plus ≥1 post-index ICS/LABA prescription. Patients were excluded if aged Results A total of 894 patients initiating FF/VI were matched to 3433 patients initiating BDP/FM. A higher proportion of patients persisted with FF/VI versus BDP/FM over 12 months (Kaplan-Meier analysis; figure 1). The likelihood of discontinuing treatment within 12 months after initiation was 31% lower for FF/VI than BDP/FM (index year-adjusted, hazard ratio=0.69; 95% CI 0.60–0.80; p Conclusion UK asthma patients initiating FF/VI were more likely to have higher persistence and better adherence to treatment than those initiating BDP/FM. GlaxoSmithKline plc. -funded study (209967/HO-18–19688).

Introduction: FRI is a validated computational fluid dynamics (CFD)-based technique using aerosol delivery performance profile, patients’ high-resolution lung CT scans and patient-derived inhalation profiles to simulate aerosol lung deposition. Aims and Objectives: To evaluate lung deposition patterns of extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium [BDP/FF/G; TRIMBOW®] pressurized metered dose inhaler (pMDI) and non-extrafine fluticasone furoate/vilanterol/umeclidinium [FluF/VI/UMEC; TRELEGY® ELLIPTA®] dry powder inhaler (DPI) in patients with stable COPD and moderate to very severe airflow obstruction. Methods: Intrathoracic depositions of the inhaled corticosteroid (ICS), long-acting β2 receptor agonist (LABA), and long-acting muscarinic antagonist (LAMA) components were calculated for each inhaler in 20 patients. Inhalation was simulated in silico using a per-patient profile derived from real life measurement. Results: Pulmonary deposition [% delivered dose] was higher for extrafine BDP than FluF (35.9 ± 6.7% vs 23.3± 4.6%) and comparable between FF and VI and between G and UMEC. Central to peripheral ratios were markedly lower for BDP, FF, and G compared to FluF, VI and UMEC, respectively (Table 1). Conclusions: FRI data indicate a higher peripheral lung (small airways) deposition with extrafine BDP/FF/G than with FluF/VI/UMEC. This may be attributed to the lower Mass Median Aerodynamic Diameter (MMAD) of BDP/FF/G.

Introduction: Persistent airflow limitation (PAL) may predict a positive clinical response to add-on long-acting muscarinic antagonist (LAMA) in asthmatics on inhaled corticosteroids and long-acting β2-receptor agonists (ICS/LABA) Objectives: We evaluated the effect of extrafine HS beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) on asthma exacerbations in a subset of patients with PAL Methods: TRIGGER was a phase III randomized, parallel group trial comparing 52-week treatment with BDP/FF/GB 800/24/50 µg/d to BDP/FF 800/24 µg/d via pressurized metered dose inhalers (pMDI) and open-label treatment consisting of BDP/FF plus tiotropium Respimat® 5 μg/d (TioR) in adult patients with uncontrolled asthma on high-dose ICS/LABA and a history of exacerbation in the past year. PAL criteria were FEV1 ≤80% of predicted normal and FEV1/FVC ≤0.7 after 400 μg salbutamol pMDI Results: 1437 subjects were randomized in 2:2:1 ratio; 880 (61.2%) met PAL criteria on BDP/FF/GB (n=357), BDP/FF (n=346), and BDP/FF+TioR (n=177), respectively. Treatment of this subgroup with BDP/FF/GB compared to BDP/FF resulted in a 25.9% and 31.8% reduction in annual moderate-severe and severe asthma exacerbations rates, respectively, (RR [95% CI] = 0.741 [0.611, 0.900], p=0.002; 0.682 [0.494; 0.940], p=0.019), vs. 12% and 20.5% reductions in the entire study population. There were no significant differences between BDP/FF/GB and BDP/FF+TioR. Conclusions: PAL is associated with a greater response to triple therapy with extrafine HS BDP/FF/GB in patients with asthma uncontrolled on high dose ICS/LABA

Introduction: Persistent airflow limitation (PAL) may predict a positive clinical response to add-on long-acting muscarinic antagonist (LAMA) in patients with asthma taking inhaled corticosteroids and long-acting β2-receptor agonists (ICS/LABA). Aims and Objectives: We evaluated the effect of extrafine MS beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) on asthma exacerbations in a subset of patients with PAL. Methods: TRIMARAN was a phase III multinational, randomized, parallel group trial comparing 52-week treatment with (BDP/FF/GB) 400/24/50 µg/d to BDP/FF 400/24 µg/d delivered via a pressurized metered dose inhaler (pMDI) in adult patients with uncontrolled asthma on medium dose ICS/LABA and a history of exacerbation in the past year. PAL was defined as an FEV1 ≤80% of predicted normal and FEV1/FVC ≤0.7 after 400 μg salbutamol pMDI. Results: 1155 subjects were randomized and 658 (57.0%) met the PAL criteria on BDP/FF/GB (n=331) and BDP/FF (n=327), respectively. Treatment of this subgroup with BDP/FF/GB compared to BDP/FF resulted in a 15.2% and 37.7% reduction in the annual rates of moderate-severe and severe asthma exacerbations respectively, (RR [95% CI] = 0.848 [0.694, 1.036], p=0.106; 0.623 [0.430; 0.902], p=0.012), vs. 15.4% (p=0.033) and 26.3% (p=0.040) reduction in the entire study population. Conclusions: In patients with asthma uncontrolled on medium dose ICS/LABA, PAL did not influence the efficacy of extrafine MS BDP/FF/GB in reducing moderate-severe exacerbations and was associated with a greater reduction in annual severe exacerbation rates.

Introduction: Previously we have reported that treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) compared to BDP/FF (TRIMARAN and TRIGGER studies) significantly reduced the annual rate of severe asthma exacerbations by 23% (p=0.008) in patients with uncontrolled asthma on ICS/LABA and history of exacerbation in the past year. Objectives: We conducted a stratified analysis of the pooled data sets to identify variables associated with the most prominent response to triple therapy. Methods: TRIMARAN and TRIGGER were two phase III randomized, multicentre, parallel group trials comparing 52-week treatment with medium strength BDP/FF/GB 400/24/50 µg/d to BDP/FF 400/24 µg/d (TRIMARAN) and high strength BDP/FF/GB 800/24/50 µg/d to BDP/FF 800/24 µg/d (TRIGGER). Results: 1146 patients on BDP/FF/GB and 1145 on BDP/FF were considered for this pre-specified pooled analysis. Statistically significant (p 400 mL following salbutamol 400 µg (0.729). Conclusions: Triple therapy with extrafine BDP/FF/GB significantly reduces severe exacerbations in asthmatics uncontrolled on ICS/LABA. Six easily identifiable traits are associated with the most prominent response to treatment and may help treatment escalation decision at the point of care.

Chronic obstructive pulmonary disease (COPD) is a condition characterised by poorly reversible airflow limitation that is generally progressive and causes serious disability. Exacerbations and co-morbidities contribute to the overall severity in individual patients. A fixed-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination of extrafine beclometasone dipropionate and formoterol fumarate (BDP/FF) has been recently approved for use in COPD. Small airway inflammation and remodelling are cardinal features of COPD; therefore, the ability of this extrafine formulation to reach the small, as well as the large, airways is likely to be therapeutically important by enabling treatment of inflammatory processes in the whole bronchial tree. The clinical development of extrafine BDP/FF has demonstrated significant benefits over extrafine FF in terms of lung function improvement and reduction of the exacerbation rate, thus supporting the beneficial effect of an ICS combined to a LABA in COPD patients. Head-to-head comparison studies versus other ICS/LABA combinations have shown that extrafine formulation enables clinical benefits to be achieved with a lower dose of ICS. Extrafine BDP/FF showed lung function and dyspneea improvements comparable to other ICS/LABAs, and a significantly faster onset of action was observed when compared with a salmeterol-containing fixed-dose combination.

BACKGROUND: The drug delivery characteristics of each inhaler/spacer combination are unique. The spacer size as well as the presence of electrostatic charge greatly influence the inhaler dose emission and in vivo delivery. Using a previously developed urinary pharmacokinetic method, we have measured the relative lung and systemic bioavailability of beclometasone dipropionate (BDP) after inhalation from 2 hydrofluroalkane-beclometasone dipropionate (HFA-BDP) formulations when used with a spacer. METHODS: 12 healthy volunteers received 8 randomized doses, separated by 7 d, of inhaled of BDP with either the Clenil pressurized metered-dose inhaler (pMDI; 250 μg) or the breath-actuated Qvar Easi-Breathe inhaler (100 μg), used alone or with a spacer. The urinary amounts of BDP excreted and retained in the spacer were assayed using a liquid chromatographic mass spectrometer. The spacer was assessed after washing with a detergent solution that was either rinsed or not rinsed with water. In addition, the aerodynamic characterization of each inhaler/spacer combination was assessed using the Andersen Cascade Impactor operated at 28 L/min using a 4-L inhalation volume. The amount of BDP deposited in the induction port, spacer, and various Anderson Cascade Impactor stages were determined. RESULTS: The in vivo 30-min urinary excretion and the in vitro fine particle dose results were only slightly affected by adding the spacer to the Clenil pMDI or the Qvar Easi-Breathe inhaler. However, the spacer significantly reduced drug particle impaction in the oropharynx and minimized deposition in the gastrointestinal tract. Therefore, using spacers with BDP inhalers is associated with a more favorable therapeutic ratio because it has little effect on lung dose, but it significantly reduced throat deposition. An improved lung deposition was achieved with non-rinsed spacers compared to spacers rinsed with water. CONCLUSION: The difference in the BDP particle size between formulations as well as spacer size greatly affected drug deposition in different regions of the respiratory tract.

Summary Background To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two studies that compared the single-inhaler extrafine combination of beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long-acting β2 agonist), and glycopyrronium (G; long-acting muscarinic antagonist) with the combination of BDP with FF. Methods Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), and from 221 sites across 17 countries (TRIGGER). The sites were a mixture of secondary and tertiary care centres and specialised investigation units. Eligible patients were adults (aged 18–75 years) with uncontrolled asthma, a history of one or more exacerbations in the previous year, and previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting β2 agonist. Enrolled patients were initially treated with BDP/FF (TRIMARAN: 100 μg BDP and 6 μg FF; TRIGGER: 200 μg BDP and 6 μg FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system with a balanced block randomisation scheme stratified by country. Patients, investigators, site staff, and sponsor staff were masked to BDP/FF/G and BDP/FF assignment. In TRIMARAN, patients were randomly assigned (1:1) to 52 weeks of BDP/FF/G (100 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (100 μg BDP and 6 μg FF), two inhalations twice daily. In TRIGGER, patients were randomly assigned (2:2:1) to 52 weeks of BDP/FF/G (200 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (200 BDP and 6 μg FF), both two inhalations twice daily, or open-label BDP/FF (200 μg BDP and 6 μg FF) two inhalations twice daily plus tiotropium 2·5 μg two inhalations once daily. Coprimary endpoints for both trials (BDP/FF/G vs BDP/FF) were pre-dose forced expiratory volume in 1 s (FEV1) at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment. These trials were registered with ClinicalTrials.gov , NCT02676076 (TRIMARAN), NCT02676089 (TRIGGER). Findings Between Feb 17, 2016, and May 17, 2018, 1155 patients in TRIMARAN were given BDP/FF/G (n=579) or BDP/FF (n=576). Between April 6, 2016, and May 28, 2018, 1437 patients in TRIGGER were given BDP/FF/G (n=573), BDP/FF (n=576), or BDP/FF plus tiotropium (n=288). Compared with the BDP/FF group, week 26 predose FEV1 improved in the BDP/FF/G group by 57 mL (95% CI 15–99; p=0·0080) in TRIMARAN and by 73 mL (26–120; p=0·0025) in TRIGGER, with reductions in the rate of moderate and severe exacerbations of 15% (rate ratio 0·85, 95% CI 0·73–0·99; p=0·033) in TRIMARAN and 12% (0·88, 0·75–1·03; p=0·11) in TRIGGER. Four patients had treatment-related serious adverse events, one in TRIMARAN in the BDP/FF/G group and three in TRIGGER—one in the BDP/FF/G and two in the BDP/FF group. Three patients in the BDP/FF/G group in TRIMARAN and two patients in TRIGGER—one in the BDP/FF/G group and one in the BDP/FF group—had adverse events leading to death. None of the deaths were considered as related to treatment. Interpretation In uncontrolled asthma, addition of a long-acting muscarinic antagonist to inhaled corticosteroid plus long-acting β2-agonist therapy improves lung function and reduces exacerbations. Funding Chiesi Farmaceutici.

The high-strength formulation of extrafine beclometasone dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid treatment, without increasing the dose of the bronchodilator, in patients who are not controlled with previous therapies. Two clinical studies have evaluated efficacy of high-strength BDP/Form as compared with another high-dose fixed combination and BDP monotherapy. Overall, data show that BDP/Form 200/6 μg improves lung function and has beneficial effects on symptoms, use of rescue medication and asthma control, with an acceptable safety profile comparable with that of high-dose fluticasone propionate/salmeterol. Therefore, BDP/Form 200/6 μg could be considered as an effective and safe treatment for patients with asthma who are not adequately controlled with high doses of inhaled corticosteroid monotherapy or medium doses of inhaled corticosteroid/long-acting β2-agonist combinations.