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Introduction: Asthma exacerbations cluster by seasons with peaks in the autumn, winter and spring. Aims and Objectives: We evaluated the effect of extra-fine beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) pressurized metered dose inhaler (pMDI) on asthma exacerbation rates during the four seasons. Methods: This was a post-hoc analysis of pooled data from two phase III multinational, randomized, parallel group trial comparing a 52-week treatment with BDP/FF/GB 400/24/50 µg/d to BDP/FF 400/24 µg/d (TRIMARAN study) and BDP/FF/GB 800/24/50 µg/d to BDP/FF 800/24 µg/d (TRIGGER study) in adult patients with uncontrolled asthma on medium or high dose ICS/LABA and a history of exacerbation in the past year. Patients with persistent airflow limitation (PAL) were identified based on FEV1 ≤80% of predicted normal and FEV1/FVC ≤0.7 after 400 μg salbutamol pMDI. Asthma exacerbations were assigned to the month corresponding to the start of the event. Seasons were normalized across northern and southern hemispheres. Results: 2291 patients were considered in this analysis, of whom 1361 had PAL. The number and rate of moderate-severe exacerbations were highest in the winter followed by autumn and spring. Reductions of moderate-severe asthma exacerbation rates with BDP/FF/GB were 11% and 23% (winter), 21% and 23% (autumn), 14% and 21% (spring), and 5 and 13% (summer) in the overall and PAL populations respectively, compared to BDP/FF. Conclusions: Treatment with extra-fine BDP/FF/GB reduces seasonal peaks of asthma exacerbations in adults with asthma uncontrolled on BDP/FF, particularly in those with PAL.

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)

The addition of a long-acting muscarinic antagonist (LAMA) is a recognised treatment option for patients whose asthma is uncontrolled with an inhaled corticosteroid (ICS) plus long-acting β2-agonist (LABA) combination [1]. The data supporting this recommendation were provided from studies in which the LAMA tiotropium was added to ICS/LABA combinations using separate inhalers [2, 3]. The use of separate inhalers, most often of different design, with contrasting instructions for use and dosing regimens is not only inconvenient for patients and healthcare providers who provide instruction on correct inhaler use, but can negatively impact treatment adherence and persistence – and therefore outcomes [4–7]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Singh reports personal fees from Chiesi, during the conduct of the study; personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Cipla, personal fees from Genentech, personal fees from GlaxoSmithKline, personal fees from Glenmark, personal fees from Menarini, personal fees from Mundipharma, personal fees from Novartis, personal fees from Peptinnovate, personal fees from Pfizer, personal fees from Pulmatrix, personal fees from Theravance, personal fees from Verona, outside the submitted work. Conflict of interest: Dr. Vele reports and I am an employee of Chiesi, the sponsor of the two studies. Conflict of interest: Dr. Kots reports and I am an employee of Chiesi, the sponsor of the two studies. Conflict of interest: Dr. Georges reports other from Chiesi USA, Inc., during the conduct of the study; other from Chiesi USA, Inc., outside the submitted work. Conflict of interest: Dr. Papi reports grants, personal fees, non-financial support and other from Chiesi, grants, personal fees, non-financial support and other from Astrazeneca, grants, personal fees, non-financial support and other from GlaxoSmithKline, grants, personal fees, non-financial support and other from Boehringer Ingelheim, personal fees and non-financial support from Menarini, personal fees and non-financial support from Novartis, personal fees and non-financial support from Zambon, grants, personal fees, non-financial support and other from Mundipharma, grants, personal fees, non-financial support and other from TEVA, personal fees and non-financial support from Sanofi, outside the submitted work. Conflict of interest: Dr. Canonica reports personal fees from A. Menarini, personal fees from Alk-Abello, personal fees from Allergy Therapeutics, personal fees from AstraZeneca-Medimmune, personal fees from Boehringer Ingelheim, personal fees from Chiesi Farmaceutici, personal fees from Genentech, personal fees from Guidotti-Malesci, personal fees from GlaxoSmithKline, personal fees from Hal Allergy, personal fees from Merck Sharp & Dome, personal fees from Mundipharma, personal fees from Novartis, personal fees from Orion, personal fees from Sanofi-Aventis, personal fees from Sanofi Genzyme/Regeneron, personal fees from Stallergenes-Greer, personal fees from Uriach Pharma, personal fees from Teva, personal fees from Valeas, personal fees from ViforPharma, outside the submitted work. Conflict of interest: Dr. Virchow reports personal fees from Chiesi , during the conduct of the study; and In the past J. Christian Virchow has ectured and received honoraria fromUstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sanofi/Regeneron, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, Zydus/Cadila and possibly othersUnd participated in advisory boards and received honoraria fromUvontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Paul-Ehrlich Institut, Regeneron, Revotar, Roche, Sanofi-Aventis, Sanofi/Regeneron, Sandoz-Hexal, TEVA, UCB/Schwarz-Pharma and possibly othersUnd received funding for research from Ýeutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, MSDUnd has advised the Bemeinsame Bundesausschuss (GBA).

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: Prostaglandin D2 acting via the DP2 receptor plays an important role in the pathogenesis of the steroid-resistant airway inflammation in severe eosinophilic asthma. We tested this hypothesis in a randomised, placebo-controlled, double-blind, parallel group proof of concept study of the effects of the DP2 antagonist timapiprant (OC459) on sputum eosinophil counts in patients with severe eosinophilic asthma. Methods: Patients meeting the ERS/ATS criteria for severe asthma, prior evidence of eosinophilic airway inflammation and screening sputum eosinophil count >3% were randomised to timapiprant 50 mg or placebo once daily for 12 weeks. Induced sputum eosinophil counts, lung function parameters, symptoms and quality of life were assessed at baseline and at 4, 8 and 12 weeks. Results: 68 patients were screened and 40 randomised. The geometric mean induced sputum eosinophil count reduced from 11.0% at baseline to 2.5% at 12 weeks with timapiprant (n=20) and from 10.7% to 6.2% with placebo (n=19). A 2.3-fold reduction (p=0.151) in sputum eosinophil level at week 12 for timapiprant compared to placebo was observed. The difference between groups for change from baseline in pre-bronchodilator FEV1 at week 12 was 127 ml (95% CI: -77 to 330 ml; p=0.214). The safety profile of timapiprant was comparable to that of placebo. Conclusions: Treatment for 12 weeks with timapiprant in severe eosinophilic asthma patients was associated with an evident reduction of airway eosinophilic inflammation and an increase in FEV1 (although not statistically significant due to the limited sample size). Studies in larger population are needed to confirm these effects.

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.

Background Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine formulations of the inhaled corticosteroid (ICS) beclomethasone dipropionate (BDP), long-acting β2-agonist formoterol fumarate (FF), and long-acting muscarinic antagonist glycopyrronium (G) is in development for asthma. Objective We sought to evaluate whether calendar season impacted the relative effect of BDP/FF/G versus BDP/FF on moderate and severe asthma exacerbations. Methods TRIMARAN and TRIGGER were double-blind 52-week studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma (Asthma Control Questionnaire-7 score ≥1.5), prebronchodilator FEV1 less than 80% predicted, history of 1 or more asthma exacerbation, who had been receiving ICS/long-acting β2-agonist for at least 4 weeks before entry. Moderate and severe asthma exacerbations were captured throughout each study. In these post hoc analyses, the annual moderate and severe exacerbation rate was calculated for each month, with rate ratios determined from events grouped by season. Results In patients who received BDP/FF alone, there was a marked seasonal effect on the occurrence of asthma exacerbations, with the rate highest in the winter months. However, the addition of the long-acting muscarinic antagonist component to BDP/FF reduced this seasonal variation, especially during the winter, such that the relative effect of BDP/FF/G versus BDP/FF was greatest in the winter (significant 20.3% reduction [P = .0008]). Reductions in the other seasons ranged between 8.6% and 12.0%. Conclusions These post hoc analyses indicate that inhaled triple therapy with extrafine BDP/FF/G reduces seasonal peaks in moderate and severe exacerbations, and confirm the overall utility of adding long-acting muscarinic antagonist to ICS/long-acting β2-agonist in the management of asthma.

Background The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

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.

Introduction Une triple association a dose fixe en particules extrafines (DPB/FF/BG dipropionate de beclometasone/fumarate de formoterol/bromure de glycopyrronium) a ete developpee en solution pour inhalation en flacon pressurise (pMDI) dans le traitement d’entretien de l’asthme insuffisamment controle sous corticosteroides inhales (CSI)/LABA. Methodes Etude de phase III internationale multicentrique, randomisee en trois bras paralleles comparant un traitement par DPB/FF/BG 200/6/12,5 μg a DPB/FF 200/6 μg en 2 inhalations × 2/j en double aveugle et, en ouvert, a DPB/FF 200/6 μg en 2 inhalations × 2/j + tiotropium Respimat® 2,5 μg 2 inhalations ×1/jour (TioR) chez des asthmatiques ≥ 18 ans, VEMS pre-BD 400 μg/j) depuis au moins 4 semaines avant la selection. Resultats Au total 1437 patients ont ete randomises (2 :2 :1) pour recevoir DPB/FF/BG (n = 573) ; DPB/FF (n = 576) ; DPB/FF + TioR (n = 288) et le taux d’achevement de l’etude est - respectivement–de 93, 93 et 91 %. Sur les deux co-criteres d’evaluation principaux, une reduction de 12 % du taux annualise d’exacerbations moderees a severes est observee en faveur du bras DPB/FF/BG versus DPB/FF (RR = 0,880 ; IC95 % [0,751 ; 1,030] ; p = 0,110) et, a S26, une amelioration de 73 mL (p = 0,003) du VEMS pre-dose toujours en faveur du bras DPB/FF/BG. Sur les principaux criteres secondaires d’evaluation, la variation depuis l’inclusion du pic du VEMS 0-3 h a S26 est egalement en faveur de la triple association (105 mL, p Conclusion Un traitement d’entretien par triple association a dose fixe en particules extrafines (DPB/FF/BG 200/6/12,5 μg) vs DPB/FF permet d’ameliorer le VEMS pre-dose et la fonction pulmonaire et de reduire (non significativement) le taux d’exacerbations moderees a severes chez des asthmatiques insuffisamment controles sous dose elevee de CSI/LABA.

SHARP (Severe Heterogeneous Asthma Research collaboration, Patient-centred) is set up to harmonise severe asthma management across Europe and unravel the heterogeneity of severe asthma in a patient-centred wayhttp://ow.ly/s1x730mwLpk

Introduction Deux etudes de phase III multicentriques, randomisees en groupes paralleles (TRIMARAN et TRIGGER) ont evalue l’efficacite et la tolerance d’un traitement sur 52 semaines par une triple association a dose fixe en particules extrafines (DPB/FF/BG : dipropionate de beclometasone/fumarate de formoterol/bromure de glycopyrronium) administree en 2 inhalations 2×/j avec - respectivement - une dose moyenne (100/6/12,5 μg) ou forte (200/6/12,5 μg) de corticosteroides inhales (CSI) versus DBP/FF chez des asthmatiques insuffisamment controles sous CSI/LABA. Sont presentes les Resultats d’une analyse combinee de ces 2 etudes, prevue au protocole, sur le taux d’exacerbations severes. Methodes Les patients inclus devaient etre âges d’au moins 18 ans : VEMS pre-BD 400 μg/j (TRIGGER), depuis au moins 4 semaines avant la selection. La severite des exacerbations etait definie par la necessite d’instaurer un traitement par corticoides par voie systemique pendant au moins 3 jours (definition ATS/ERS 2009). Resultats Au total 1155 patients ont ete randomises dans l’etude TRIMARAN pour recevoir DPB/FF/BG ou DPB/FF (1 :1) et 1437 dans l’etude TRIGGER (2 :2 :1 pour recevoir DPB/FF/BG, DPB/FF ou DPB/FF + Tiotropium). Les resultats portent sur une population de 2 291 patients inclus dans l’analyse combinee : 53,1 ans (12,2) de moyenne d’âge (ET), IMC moyen a 28,2 (5,2) kg/m2, 32,6 % (21,9) de reversibilite au salbutamol et 60,8 % de femmes. Il a ete observe une reduction significative de 23 % en faveur de la triple association DPB/FF/BG sur le taux annualise d’exacerbations severes (RR = 0,770 ; IC95 % [0,636 ; 0,933] ; p = 0,008) et une reduction non significative de 23,7 % du nombre de jours d’utilisation de corticoides par voie systemique (RR = 0,763 ; IC95 % [0,558 ; 1,042] ; p = 0,089) versus la double association DPB/FF. Conclusion Un traitement d’entretien par triple association a dose fixe en particules extrafines (DPB/FF/BG) permet de reduire significativement le taux d’exacerbations severes et est associe a une diminution du nombre de jours sans utilisation de corticoides systemiques chez des asthmatiques insuffisamment controles sous dose moyenne ou forte de CSI/LABA.

BACKGROUND: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalised management approach can be provided.OBJECTIVES: We stratified patients with moderate-to-severe asthma based on clinico-physiological parameters and performed an -omics analysis of sputum.METHODS: Partition-around-medoid clustering was applied to a training set of 266 asthma participants from the European U-BIOPRED adult cohort using 8 pre-specified clinic-physiological variables. This was repeated in a separate validation set of 152 asthmatics. The clusters were compared based on sputum proteomic and transcriptomic data.RESULTS: Four reproducible and stable clusters of asthmatics were identified. The training set cluster T1 consists of well-controlled moderate-to-severe asthmatics, while cluster T2 is a group of late-onset severe asthmatics with history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of non-smokers. Cluster T4 is predominantly composed of obese female uncontrolled severe asthmatics with increased exacerbations, but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters, T2, T3 and T4, had higher sputum eosinophilia than T1 with no differences in sputum neutrophil counts, exhaled nitric oxide and serum IgE levels.CONCLUSION: Clustering based on clinico-physiological parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.CLINICAL IMPLICATIONS: The definition of four distinct clusters of asthma linked to different pathobiological pathways provides a better template for the phenotyping and personalised treatment of severe asthma, where high unmet needs remain.CAPSULE SUMMARY: Unsupervised clustering of asthma on clinical features alone has led to the definition of four phenotypes. Sputum 'omics' analysis has revealed different biological pathways pointing towards potential new treatments.

Background: CHF 5993 pMDI is a new extrafine fixed dose combination of Beclometasone Dipropionate (BDP), Formoterol Fumarate (FF) and Glycopyrronium bromide (GB), being developed as twice-daily treatment in COPD and asthma. We investigated the pharmacokinetics, safety and tolerability of CHF5993 pMDI in renal impaired (RI) patients. Methods: Non-randomised, open-label, parallel group study. Four inhalations of CHF5993 pMDI (BDP/FF/GB total dose 400/24/100 µg) were administered to mild, moderate and severe RI patients and to matched (in terms of sex, age and BMI) healthy volunteers (HV). Results: Nine mild, 7 moderate, 9 severe RI patients and 17 HVs aged 40-64 years were treated. GB systemic exposure increased with decreasing renal function, mainly in severe RI patients. GB renal clearance decreased proportionally with renal function. The degree of renal impairment had no impact on formoterol systemic exposure, while C max was reduced by about 50% in all groups of RI patients as compared to HVs. No clear relationship between renal function and renal clearance of total formoterol was found. B17MP (BDP main metabolite) systemic exposure was lower in RI patients as compared to HVs; however, differences tended to decrease with increasing degree of renal impairment. CHF5993 pMDI showed good and similar safety profiles in all RI and HVs as assessed by adverse events, laboratory parameters, vital signs and ECG. Conclusion: Despite a higher exposure to GB in severe RI patients, the GB non-renal clearance offsets the reduced elimination in mild and moderate RI patients. Therefore, CHF5993 pMDI displays a good safety profile without relevant differences between groups.