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The interaction of light with objects and media moving at relativistic and superluminal speeds enables unconventional phenomena such as Fresnel drag, Hawking radiation, and light amplification. Synthetic motion, facilitated by modulated internal degrees of freedom, enables the study of relativistic phenomena unrestricted by the speed of light. In this study, we investigate synthetically moving apertures created by high-contrast reflectivity modulations, which are generated by ultrafast laser pulses on a subwavelength thin film of indium tin oxide. The space-time diffraction of a weaker probe beam reveals a complex, non-separable spatio-temporal transformation, where changes in the frequency of the wave are correlated to changes in its momentum. By using schemes of continuous or discrete modulation we demonstrate tunable frequency-momentum diffraction patterns with gradients that depend upon the relative velocity between the modulation and the probe wave. The diffraction patterns are matched by operator-based theory and the gradients are analytically predicted using a super-relativistic Doppler model, where the modulation is described as a superluminally moving scattering particle. Our experiments open a path towards mimicking relativistic mechanics and developing complex and programmable spatio-temporal transformations of light. Relativistic motion enables unusual light-matter interactions. Here, authors use ultrafast lasers to create synthetically moving reflectivity patterns that diffract light in space and time, enabling tuneable frequency-momentum control, mimicking scattering from a sub-, or super-, luminal object.

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. 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, FEV <50%, and an exacerbation history. We measured the time to first CID and to sustained CID, an endpoint combining FEV , St George's Respiratory Questionnaire (SGRQ), moderate-to-severe exacerbations, and death. The time to first CID was based on the first occurrence of any of the following: a decrease of ≥100 mL from baseline in FEV , an increase of ≥4 units from baseline in SGRQ total score, the occurrence of a moderate/severe COPD exacerbation, or death. The time to sustained CID was defined as: a CID in FEV and/or SGRQ total score maintained at all subsequent visits, an exacerbation, or death. Extrafine BDP/FF/G significantly extended the time to first CID vs BDP/FF (HR 0.61, <0.001), tiotropium (0.72, <0.001), and IND/GLY (0.82, <0.001), and significantly extended the time to sustained CID vs BDP/FF (HR 0.64, <0.001) and tiotropium (0.80, <0.001), with a numerical extension vs IND/GLY. In patients with symptomatic COPD, FEV <50%, and an exacerbation history, extrafine BDP/FF/G delayed disease deterioration compared with BDP/FF, tiotropium, and IND/GLY. The studies are registered in ClinicalTrials.gov: TRILOGY, NCT01917331; TRINITY, NCT01911364; TRIBUTE, NCT02579850.

The GOLD 2017 strategy document recommends that the pharmacological management of COPD patients be based on the risk of future exacerbations and the severity of symptoms. A threshold of two moderate exacerbations or one hospitalization is used to define high-risk patients. The FORWARD study was a randomized, double-blind, parallel-group trial that compared 48 weeks' treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP-FF) versus FF in severe COPD patients with a history of one or more exacerbations in the previous year. The new GOLD 2017 recommendations mean that many patients in the FORWARD study are now reclassified as GOLD B. We conducted a post hoc analysis of the FORWARD study, in order to investigate the effects of extrafine BDP/FF in patients with one exacerbation in the previous year, focusing on those categorized as group B using the GOLD 2017 definition. The analysis showed a 35% reduction in exacerbation rate with an inhaled corticosteroid (ICS) + long-acting β-agonist (LABA) versus LABA. We propose that ICS-LABA treatment is a therapeutic option for COPD patients with one exacerbation in the previous year.

Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple). For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) of less than 50%, at least one moderate-to-severe COPD exacerbation in the previous 12 months, and a COPD Assessment Test total score of at least 10. After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium, patients were randomised (2:2:1) using a interactive response technology system to 52 weeks treatment with tiotropium, fixed triple, or open triple. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was moderate-to-severe COPD exacerbation rate. The key secondary endpoint was change from baseline in pre-dose FEV1 at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364. Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0·46 (95% CI 0·41–0·51) for fixed triple, 0·57 (0·52–0·63) for tiotropium, and 0·45 (0·39–0·52) for open triple; fixed triple was superior to tiotropium (rate ratio 0·80 [95% CI 0·69–0·92]; p=0·0025). For week 52 pre-dose FEV1, fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p<0·0001) and non-inferior to open triple (−0·003L [–0·033 to 0·027]; p=0·85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple. In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV1 of less than 50%, and a history of exacerbations. Chiesi Farmaceutici SpA.

Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment. This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 μg/43 μg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 μg/5 μg/9 μg) twice per day or one inhalation of IND/GLY (85 μg/43 μg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850. Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45–0·57) for BDP/FF/G and 0·59 per patient per year (0·53–0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723–0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY. In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia. Chiesi Farmaceutici.

Few data are available for the efficacy of “triple therapy” with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We designed this study to assess efficacy of single-inhaler combination of an extra fine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB) in COPD compared with beclometasone dipropionate and formoterol fumarate (BDP/FF) treatment. TRILOGY was a randomised, parallel group, double-blind, active-controlled study done in 159 sites across 14 countries. The sites were a mixture of primary, secondary, and tertiary care providers, and specialist investigation units. Eligible patients with COPD had post-bronchodilator forced expiratory volume in 1 s (FEV1) of lower than 50%, one or more moderate-to-severe COPD exacerbation in the previous 12 months, COPD Assessment Test total score of 10 or more, and a Baseline Dyspnea Index focal score of 10 or less. Patients who met the inclusion and exclusion criteria at screening entered a 2-week open-label run-in period where they received beclometasone dipropionate (100 μg) and formoterol fumarate (6 μg) in two actuations twice daily. Patients were then randomly assigned (1:1) with an interactive response technology system to either continue BDP (100 μg) and FF (6 μg) or step-up to BDP (100 μg), FF (6 μg), and GB (12·5 μg) in two actuations twice daily for 52 weeks via pressurised metered-dose inhaler. The three co-primary endpoints were pre-dose FEV1, 2-h post-dose FEV1, and Transition Dyspnea Index (TDI) focal score, all measured at week 26 in the intention-to-treat population (all patients who were randomly assigned and received at least one dose of study drug and had at least one post-baseline efficacy assessment). Safety outcomes were measured in the safety population (all patients who were randomly assigned and received at least one dose of study drug). Secondary endpoints included moderate-to-severe COPD exacerbation rate over 52 weeks. This study is registered with ClinicalTrials.gov, number NCT01917331. Between March 21, 2014, and Jan 14, 2016, 1368 patients received either BDP/FF/GB (n=687) or BDP/FF (n=681). At week 26, BDP/FF/GB improved pre-dose FEV1 by 0·081 L (95% CI 0·052–0·109; p<0·001) and 2-h post-dose FEV1 by 0·117 L (0·086–0·147; p<0·001) compared with BDP/FF. Mean TDI focal scores at week 26 were 1·71 for BDP/FF/GB and 1·50 for BDP/FF, with a difference of 0·21 (95% CI −0·08 to 0·51; p=0·160). Adjusted annual moderate-to-severe exacerbation frequencies were 0·41 for BDP/FF/GB and 0·53 for BDP/FF (rate ratio 0·77 [95% CI 0·65–0·92]; p=0·005), corresponding to a 23% reduction in exacerbations with BDP/FF/GB compared with BDP/FF. Adverse events were reported by 368 (54%) patients with BDP/FF/GB and 379 (56%) with BDP/FF. One serious treatment-related adverse event occurred (atrial fibrillation) in a patient in the BDP/FF/GB group. We provide evidence for the clinical benefits of stepping up patients with COPD from an inhaled corticosteroid/long-acting β2-agonist combination treatment to triple therapy using a single inhaler. Chiesi Farmaceutici SpA.

Background Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. Methods Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study. Results CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 μg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. Conclusions Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. Trial registration ClinicalTrial.gov, EudraCT, 2015–005550-35 . Registered 15 July 2016.

Methods: TRINITY was a phase Ill, double-blind, 52-week study where 2691 severe/very severe COPD patients with a history of exacerbations were randomised to receive CHF5993 (fixed dose combination of the ICS beclometasone dipropionate, the LABA formoterol fumarate and the LAMA glycopyrronium bromide) or Tiotropium or a fixed dose combination of beclometasone dipropionate and formoterol fumarate (Foster®) + Tiotropium. Conclusion: The results of this pre-planned subgroup analysis showed that a novel extrafine triple FDC of BDP/FF/GB confers a superior clinical benefit compared to the free combination of Foster® + Tiotropium in a subgroup of COPD patients at higher risk for exacerbations.

RationaleTreatment with extrafine triple therapy in a single inhaler has beneficial effects compared to LAMA monotherapy on lung function and symptoms. This analysis focuses on rescue medication use (as this is associated with symptoms) and lung function responder analysis identifying clinically relevant effects.MethodsIn this 52 week multicentre, randomised, double-blind, active-controlled study, 2691 patients with severe to very severe COPD, exacerbations history, and CAT total score ≥10 were randomised (2:2:1) to tiotropium, fixed triple (beclometasone/formoterol/glycopyrronium), or free triple (beclometasone/formoterol+tiotropium). Secondary endpoints included FEV1 responders at week 26 and 52 using different thresholds for response and change from baseline in average use of rescue medication.ResultsBoth fixed and free triple FEV1 responder percentages were significantly greater than tiotropium at weeks 26 and 52 regardless of the threshold used to define the response (p<0.001 for all analyses). At 26 weeks the proportion of responders were 48.0% (fixed triple) and 48.1% (free triple) for the 50 ml threshold, and 36.7% and 34.8% at the higher 120 mL threshold, with similar Results at week 52. Corresponding FEV1 responder percentages for tiotropium were lower at the 50 mL threshold (35.7% and 34.8%, at weeks 26 and 52 respectively) and 120 mL threshold (25.3% and 24.8%, respectively). In terms of average percentage of days without rescue medication use over 52 weeks, all treatments showed statistically significant increases from baseline which were more marked with fixed and free triple (13.9 [95%CI: 12;15.8] and 14.8% [95%CI: 12.1;17.4] respectively) compared to 5.2% [95%CI: 3.3;7.1] for tiotropium alone (p<0.001) and no difference observed between fixed and free triple with an adjusted mean difference of −0.8% [95% CI: −4.1;2.4] (p=0.616). Average use of rescue medication with both fixed and free triple treatments over 52 weeks compared to tiotropium alone was reduced by 0.6 [95%CI: 0.4;0.7] and 0.6 [95%CI: 0.5;0.8] puffs/day, respectively (p<0.001).ConclusionsExtrafine triple therapy in a single inhaler provides superior clinical benefits in severe to very severe COPD patients in terms of lung function (by individual responder analysis) and rescue medication use compared with tiotropium alone.Please refer to page A260 for declarations of interest in relation to abstract P271.

RationaleEfficacy and safety of extrafine fixed triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; 100/6/12.5 mcg, two actuations BID via pMDI; ‘fixed triple’) has been recently demonstrated in two phase III trials. Fixed triple has shown superiority in improving lung function and reducing moderate/severe exacerbations versus BDP/FF (Fostair 100/6 mcg, two actuations BID via pMD; TRILOGY – Singh et al. Lancet 2016; 388: 963–73) and versus tiotropium (18 mcg one inhalation OD via DPI; TRINITY – Vestbo et al. Lancet 2017; 389: 1919–29). Increase in pneumonia risk associated with ICS containing medications is a known class effect. The risk/benefit balance of extrafine fixed triple was evaluated by comparing variations in pneumonia and exacerbation events.MethodsInformation on moderate/severe exacerbations and confirmed pneumonia was extracted from TRINITY and TRILOGY. A frequency plot was generated considering days in the study versus cumulative number of events.ResultsIn TRILOGY study, the number of recorded events was 288 exacerbations (rate: 0.448 exacerbations per patient per year) versus 25 pneumonias (rate: 0.039 events per patient per year) with fixed triple and 353 exacerbations (0.565) versus 18 pneumonias (0.029) with Fostair (figure 1A). In TRINITY study, the number of events was 485 exacerbations (0.472) versus 30 pneumonias (0.029) with fixed triple and 569 exacerbations (0.583) versus 20 pneumonias (0.020) with tiotropium (figure 1B). Overall, treatment with fixed triple therapy reduced exacerbations by 65 events compared to Fostair (adjusted rate ratio: 0.773, p=0.005) and by 84 events compared to tiotropium (0.801, p=0.003). No fatal pneumonias occurred in TRILOGY while 5 pneumonias led to death in TRINITY (1 with fixed triple versus 4 with tiotropium). All pneumonias were classified as non-related to treatment.ConclusionsThis analysis confirms that, in two independent populations of COPD patients treated with an ICS containing extrafine fixed triple combination, the number of incident pneumonia remains very small compared to that of moderate/severe exacerbations. The benefit observed in reducing the absolute number of exacerbations outweighs the increase observed in absolute number of pneumonias, thus confirming the positive risk benefit balance of extrafine fixed triple in severe/very severe COPD patients.Please refer to page A260 for declarations of interest in relation to abstract P273.