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Dave Singh - One of the best experts on this subject based on the ideXlab platform.

  • lung function improvements following inhaled indacaterol Glycopyrronium mometasone furoate are independent of dosing time in asthma patients a randomised trial
    ERJ Open Research, 2021
    Co-Authors: Jutta Beier, Dave Singh, Henrik Watz, Zuzana Diamant, Jens M Hohlfeld, Pascale Pinot, Ieuan Jones
    Abstract:

    Once-daily asthma treatment should prevent night-time deterioration, irrespective of the time of dosing. IND/GLY/MF, a fixed-dose combination of inhaled indacaterol acetate (IND, long-acting β2-agonist (LABA)), Glycopyrronium Bromide (GLY, long-acting muscarinic antagonist) and mometasone furoate (MF, inhaled corticosteroid (ICS)) delivered by Breezhaler, is indicated in adult asthma patients inadequately controlled on LABA/ICS. A randomised, double-blind, placebo-controlled, three-period, crossover, phase II study was performed to investigate the bronchodilator effect of IND/GLY/MF (150/50/80 μg) dosed morning and evening versus placebo in patients with mild-moderate asthma. The primary end-point was weighted mean forced expiratory volume in 1 s (FEV1) over 24 h following 14 days of IND/GLY/MF dosed a.m. and p.m. versus placebo. Secondary end-points included the effect of dosing time on peak expiratory flow (PEF) and safety/tolerability. Of 37 randomised patients (age 18-72 years; 21 male, 16 female) 34 completed all three treatment periods. At screening, median (range) pre-bronchodilator FEV1 was 75.8% (60-96%). Patients were using stable low- (83.8%) or medium-dose (16.2%) ICS. Morning and evening dosing of IND/GLY/MF improved FEV1 (area under the curve from 0 to 24 h) by 610 mL (90% CI 538-681 mL) and 615 mL (90% CI 544-687 mL), respectively, versus placebo. Mean PEF over 14 days increased by 70.7 L·min-1 (90% CI 60.5-80.9 L·min-1) following a.m. dosing, and by 59.7 L·min-1 (90% CI 49.5-69.9 L·min-1) following p.m. dosing of IND/GLY/MF versus placebo. IND/GLY/MF demonstrated a safety profile comparable with placebo. Once-daily inhaled IND/GLY/MF was well tolerated and provided sustained lung function improvements over 24 h, irrespective of a.m. or p.m. dosing, in patients with mild-moderate asthma.

  • Lung function improvements following inhaled indacaterol/Glycopyrronium/mometasone furoate are independent of dosing time in asthma patients: a randomised trial
    'European Respiratory Society (ERS)', 2021
    Co-Authors: Jutta Beier, Dave Singh, Henrik Watz, Zuzana Diamant, Jens M Hohlfeld, Pascale Pinot, Ieuan Jones, Hanns-christian Tillmann
    Abstract:

    Once-daily asthma treatment should prevent night-time deterioration, irrespective of the time of dosing. IND/GLY/MF, a fixed-dose combination of inhaled indacaterol acetate (IND, long-acting β2-agonist (LABA)), Glycopyrronium Bromide (GLY, long-acting muscarinic antagonist) and mometasone furoate (MF, inhaled corticosteroid (ICS)) delivered by Breezhaler, is indicated in adult asthma patients inadequately controlled on LABA/ICS. A randomised, double-blind, placebo-controlled, three-period, crossover, phase II study was performed to investigate the bronchodilator effect of IND/GLY/MF (150/50/80 μg) dosed morning and evening versus placebo in patients with mild-moderate asthma. The primary end-point was weighted mean forced expiratory volume in 1 s (FEV1) over 24 h following 14 days of IND/GLY/MF dosed a.m. and p.m. versus placebo. Secondary end-points included the effect of dosing time on peak expiratory flow (PEF) and safety/tolerability. Of 37 randomised patients (age 18–72 years; 21 male, 16 female) 34 completed all three treatment periods. At screening, median (range) pre-bronchodilator FEV1 was 75.8% (60–96%). Patients were using stable low- (83.8%) or medium-dose (16.2%) ICS. Morning and evening dosing of IND/GLY/MF improved FEV1 (area under the curve from 0 to 24 h) by 610 mL (90% CI 538–681 mL) and 615 mL (90% CI 544–687 mL), respectively, versus placebo. Mean PEF over 14 days increased by 70.7 L·min−1 (90% CI 60.5–80.9 L·min−1) following a.m. dosing, and by 59.7 L·min−1 (90% CI 49.5–69.9 L·min−1) following p.m. dosing of IND/GLY/MF versus placebo. IND/GLY/MF demonstrated a safety profile comparable with placebo. Once-daily inhaled IND/GLY/MF was well tolerated and provided sustained lung function improvements over 24 h, irrespective of a.m. or p.m. dosing, in patients with mild–moderate asthma

  • lung function improvements following inhaled indacaterol Glycopyrronium mometasone furoate are independent of dosing time in asthma patients a randomised trial
    ERJ Open Research, 2020
    Co-Authors: Jutta Beier, Dave Singh, Henrik Watz, Zuzana Diamant, Jens M Hohlfeld, Pascale Pinot, Ieuan Jones
    Abstract:

    Once-daily asthma treatment should prevent night-time deterioration, irrespective of the time of dosing. IND/GLY/MF, a fixed-dose combination of inhaled indacaterol acetate (IND, long-acting β2-agonist), Glycopyrronium Bromide (GLY, long-acting muscarinic antagonist), and mometasone furoate (MF, inhaled corticosteroid [ICS]) delivered by Breezhaler®, is indicated in adult asthma patients inadequately controlled on LABA/ICS. A randomised, double-blind, placebo-controlled, three-period, crossover, phase II study was performed to investigate the bronchodilator effect of IND/GLY/MF (150/50/80 μg) dosed am and pm versus placebo in patients with mild-moderate asthma. The primary endpoint was weighted mean forced expiratory volume in 1 s (FEV1) over 24 h following 14 days of IND/GLY/MF dosed am and pm versus placebo. Secondary endpoints included the effect of dosing time on peak expiratory flow (PEF) and safety/tolerability. Of 37 randomised patients (age 18–72 years, 21 male, 16 female) 34 completed all three treatment periods. At screening, median (range) pre-bronchodilator FEV1 was 75.8% (60–96). Patients were using stable low- (83.8%) or medium-dose (16.2%) ICS. Morning and evening dosing of IND/GLY/MF improved FEV1 (AUC0–24h) by 610 mL (90% CI: 538, 681) and 615 mL (90% CI: 544, 687), respectively, versus placebo. Mean PEF over 14 days increased by 70.7 L·min−1 (90% CI: 60.5, 80.9) following am dosing, and by 59.7 L·min−1 (90% CI: 49.5, 69.9) following pm dosing of IND/GLY/MF versus placebo. IND/GLY/MF demonstrated a safety profile comparable with placebo. Once-daily inhaled IND/GLY/MF was well tolerated and provided sustained lung function improvements over 24 h, irrespective of am or pm dosing, in patients with mild-moderate asthma.

  • evaluation of systemic absorption and bronchodilator effect of Glycopyrronium Bromide delivered by nebulizer or a dry powder inhaler in subjects with chronic obstructive pulmonary disease
    Respiratory Research, 2019
    Co-Authors: Brian Leaker, Dave Singh, Thomas Goodin, Grant C Nicholson, Blanka Hezelova, Ayca Ozolgodfrey, Gerald Galluppi, Peter J Barnes
    Abstract:

    Effective bronchodilator therapy depends upon adequate drug deposition in the lung. COPD patients who are unable to administer medications efficiently with conventional inhalers may benefit from the use of a nebulizer device. The aim of this study was to evaluate the systemic bioavailability and bronchodilator response of Glycopyrronium Bromide (GLY) administered by a novel nebulizer (eFlow® closed system [CS] vibrating membrane nebulizer) or dry powder inhaler (DPI) in subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD). In this randomized, open-label, single-dose, five-way crossover study, subjects received a sequence of either 50 μg GLY delivered by eFlow CS nebulizer (GLY/eFlow) or 63 μg GLY delivered by DPI (GLY/DPI), with and without activated charcoal, followed by intravenous infusion of 50 μg GLY with a washout period of 7 days between doses. Endpoints included plasma pharmacokinetics, safety and efficacy. The mean (± SD) baseline predicted forced expiratory volume in 1 s (FEV1) of the 30 subjects who completed the study was 51 ± 15%, with a FEV1/forced vital capacity ratio of 50 ± 11%. Without charcoal, the absolute systemic bioavailability of GLY/eFlow and GLY/DPI were approximately 15 and 22%, respectively. Changes from baseline in FEV1 at 60 min post-dose, without administration of charcoal, were 0.180 L and 0.220 L for GLY/eFlow and GLY/DPI, respectively; FEV1 improvements were similar when charcoal was administered (0.220 L for both GLY/eFlow and GLY/DPI). There were no significant differences in spirometry between the two devices. Fewer subjects administered GLY/eFlow reported adverse events (n = 15) than GLY/DPI (n = 18). After single doses, GLY/DPI delivered numerically higher peak and steady state levels of drug than did GLY/eFlow. Nebulized GLY produced similar bronchodilation but lower systemic levels of drug than GLY/DPI. Slightly higher number of subjects reported adverse events with GLY/DPI than with GLY/eFlow. Nebulized GLY may offer an effective alternative to patients with COPD not adequately treated with other devices. NCT02512302 (ClinicalTrials.gov). Registered 28 May 2015.

  • triple therapy in copd new evidence with the extrafine fixed combination of beclomethasone dipropionate formoterol fumarate and Glycopyrronium Bromide
    International Journal of Chronic Obstructive Pulmonary Disease, 2017
    Co-Authors: Dave Singh, Massimo Corradi, Mario Scuri, Stefano Petruzzelli, Monica Spinola, Alberto Papi, Omar S Usmani, Jorgen Vestbo
    Abstract:

    The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a "step-up" therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/Glycopyrronium Bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

Mario Scuri - One of the best experts on this subject based on the ideXlab platform.

  • P276 Cardiovascular safety of extrafine single inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and Glycopyrronium Bromide in copd: results of safety analysis from the trilogy and trinity studies
    Thorax, 2017
    Co-Authors: Mario Scuri, Massimo Corradi, I Montagna, Stefano Vezzoli, G. Cohuet, A Muraro, David Singh, C Francisco, Stefano Petruzzelli
    Abstract:

    Rationale COPD often co-exists with other chronic diseases that can contribute to patients’ health status and prognosis. In particular, patients with COPD are at greater risk of cardiovascular disease compared with age and sex-matched controls. Methods Two 52 week multi-centre, randomised, double-blind, active-controlled studies recruited patients with symptomatic COPD, severe to very severe airflow limitation, and an exacerbation history. In TRILOGY, patients were randomised (1:1) to an extrafine fixed triple combination of beclometasone dipropionate, formoterol fumarate, and Glycopyrronium Bromide (BDP/FF/GB; 100/6/12.5 mcg, two actuations twice daily [BID] via pressurised metered dose inhaler [pMDI]; ‘fixed triple’) or an extrafine fixed combination of BDP/FF (100/6 mcg, two actuations BID via pMDI; Fostair) (Singh et al. Lancet 2016; 388: 963–73). In TRINITY patients were randomised 2:2:1 to BDP/FF/GB, tiotropium (18 mcg once daily via single-dose dry powder inhaler [SDDPI]), or BDP/FF+tiotropium: free triple (Vestbo et al. Lancet 2017; 389: 1919–29). In this analysis, we evaluated the occurrence of Major Adverse Cardiovascular Events (MACEs). MACEs included acute myocardial infarction, stroke, cardiovascular death, arrhythmias, and heart failure. Results MACE incidence and rate in the two BDP/FF/GB groups was similar to the BDP/FF and tiotropium groups (Table 1). The majority of reported MACEs were severe in intensity, with a slightly higher percentage of fatal events in the Tiotropium only group. Importantly, in patients with relevant concomitant cardiovascular diseases, the trend was similar to that seen in the overall populations. None of the other subgroup analyses (by age, spacer use and gender) highlighted relevant differences in the safety profiles compared with the overall population. Conclusions These Results provide further reassurance that the additional clinical benefits of this extrafine fixed triple compared to standard treatment are not associated with a greater impact on the cardiovascular safety in severe to very severe COPD patients, further supporting its positive benefit/risk ratio. Importantly, the presence of concomitant cardiac comorbidities did not influence the rate of cardiovascular events. Please refer to page A261 for declarations of interest in relation to abstract P276.

  • triple therapy in copd new evidence with the extrafine fixed combination of beclomethasone dipropionate formoterol fumarate and Glycopyrronium Bromide
    International Journal of Chronic Obstructive Pulmonary Disease, 2017
    Co-Authors: Dave Singh, Massimo Corradi, Mario Scuri, Stefano Petruzzelli, Monica Spinola, Alberto Papi, Omar S Usmani, Jorgen Vestbo
    Abstract:

    The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a "step-up" therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/Glycopyrronium Bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

  • chf5993 pmdi extrafine beclometasone dipropionate bdp formoterol fumarate ff Glycopyrronium Bromide gb reduces clinically important deteriorations cid in copd post hoc analysis of trilogy study
    European Respiratory Journal, 2017
    Co-Authors: Dave Singh, Mario Scuri, Stefano Petruzzelli, Stefano Vezzoli, A Muraro, Monica Spinola, Alberto Papi, Jorgen Vestbo
    Abstract:

    Rationale: CID is a composite endpoint assessing relevant deteriorations in COPD that may be useful to improve disease management. We report the results of a post-hoc analysis of TRILOGY study comparing the effect on CID of CHF5993 pMDI vs. extrafine BDP/FF pMDI (Foster®) in COPD patients. Methods: CID was defined as 1) decrease ≥100 mL from baseline in FEV1, 2) deterioration ≥4 units from baseline in SGRQ score, 3) deterioration ≥1 unit from baseline in TDI score, 4) occurrence of a moderate/severe COPD exacerbation (acute worsening of COPD symptoms requiring oral corticosteroids, antibiotics, or hospitalization), 5) death. Sustained CID (CID maintained at all subsequent visits), and time to first deterioration of TDI component were also assessed. Results: Compared to Foster®, CHF5993 pMDI significantly prolonged time to first CID (HR: 0.62; p Conclusions: CHF5993 pMDI provides superior efficacy vs Foster® in reducing deterioration of lung function, health status and exacerbations, strengthening the role of this novel triple combination in the management of COPD

  • bronchodilator efficacy of extrafine Glycopyrronium Bromide the glyco 2 study
    International Journal of Chronic Obstructive Pulmonary Disease, 2017
    Co-Authors: Dave Singh, Fabrizia Mariotti, Mario Scuri, Stefano Vezzoli, A Muraro, Sara Collarini, Daniela Acerbi
    Abstract:

    An extrafine formulation of the long-acting muscarinic antagonist Glycopyrronium Bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 μg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 μg once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 μg. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV1) area under the curve (AUC0-12h) and peak FEV1, with a trend toward greater efficacy with higher GB dose. All adverse events were mild-moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose-response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV1 on Day 7 (primary) were 115, 142 and 136 mL for GB 12.5, 25 and 50 μg BID, respectively (all P<0.001). GB 25 and 50 μg BID were superior (P<0.05) to GB 12.5 μg BID for pre-dose morning FEV1 on Day 8. For this endpoint, GB 25 and 50 μg BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV1 peak and AUC0-12h with all GB doses and placebo (all P<0.001). All adverse events were mild-moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 μg BID is the optimal dose in patients with COPD.

  • single inhaler extrafine triple therapy versus long acting muscarinic antagonist therapy for chronic obstructive pulmonary disease trinity a double blind parallel group randomised controlled trial
    The Lancet, 2017
    Co-Authors: Massimo Corradi, I Montagna, Stefano Vezzoli, G. Cohuet, Catherine Francisco, Jorgen Vestbo, Alberto Papi, Viktor Blazhko, Mario Scuri
    Abstract:

    Summary Background 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). Methods For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 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 FEV 1 at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364. Findings 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 FEV 1 , fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p Interpretation In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV 1 of less than 50%, and a history of exacerbations. Funding Chiesi Farmaceutici SpA.

Jorgen Vestbo - One of the best experts on this subject based on the ideXlab platform.

  • triple therapy in copd new evidence with the extrafine fixed combination of beclomethasone dipropionate formoterol fumarate and Glycopyrronium Bromide
    International Journal of Chronic Obstructive Pulmonary Disease, 2017
    Co-Authors: Dave Singh, Massimo Corradi, Mario Scuri, Stefano Petruzzelli, Monica Spinola, Alberto Papi, Omar S Usmani, Jorgen Vestbo
    Abstract:

    The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a "step-up" therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/Glycopyrronium Bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

  • chf5993 pmdi extrafine beclometasone dipropionate bdp formoterol fumarate ff Glycopyrronium Bromide gb reduces clinically important deteriorations cid in copd post hoc analysis of trilogy study
    European Respiratory Journal, 2017
    Co-Authors: Dave Singh, Mario Scuri, Stefano Petruzzelli, Stefano Vezzoli, A Muraro, Monica Spinola, Alberto Papi, Jorgen Vestbo
    Abstract:

    Rationale: CID is a composite endpoint assessing relevant deteriorations in COPD that may be useful to improve disease management. We report the results of a post-hoc analysis of TRILOGY study comparing the effect on CID of CHF5993 pMDI vs. extrafine BDP/FF pMDI (Foster®) in COPD patients. Methods: CID was defined as 1) decrease ≥100 mL from baseline in FEV1, 2) deterioration ≥4 units from baseline in SGRQ score, 3) deterioration ≥1 unit from baseline in TDI score, 4) occurrence of a moderate/severe COPD exacerbation (acute worsening of COPD symptoms requiring oral corticosteroids, antibiotics, or hospitalization), 5) death. Sustained CID (CID maintained at all subsequent visits), and time to first deterioration of TDI component were also assessed. Results: Compared to Foster®, CHF5993 pMDI significantly prolonged time to first CID (HR: 0.62; p Conclusions: CHF5993 pMDI provides superior efficacy vs Foster® in reducing deterioration of lung function, health status and exacerbations, strengthening the role of this novel triple combination in the management of COPD

  • single inhaler extrafine triple therapy versus long acting muscarinic antagonist therapy for chronic obstructive pulmonary disease trinity a double blind parallel group randomised controlled trial
    The Lancet, 2017
    Co-Authors: Massimo Corradi, I Montagna, Stefano Vezzoli, G. Cohuet, Catherine Francisco, Jorgen Vestbo, Alberto Papi, Viktor Blazhko, Mario Scuri
    Abstract:

    Summary Background 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). Methods For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 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 FEV 1 at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364. Findings 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 FEV 1 , fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p Interpretation In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV 1 of less than 50%, and a history of exacerbations. Funding Chiesi Farmaceutici SpA.

  • single inhaler triple therapy versus inhaled corticosteroid plus long acting β2 agonist therapy for chronic obstructive pulmonary disease trilogy a double blind parallel group randomised controlled trial
    The Lancet, 2016
    Co-Authors: Dave Singh, Massimo Corradi, Mario Scuri, I Montagna, Stefano Vezzoli, G. Cohuet, Ilona Pavlisova, Catherine Francisco, Jorgen Vestbo
    Abstract:

    Summary Background 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. Methods 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 (FEV 1 ) 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 FEV 1 , 2-h post-dose FEV 1 , 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. Findings 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 FEV 1 by 0·081 L (95% CI 0·052–0·109; p 1 by 0·117 L (0·086–0·147; p Interpretation We provide evidence for the clinical benefits of stepping up patients with COPD from an inhaled corticosteroid/long-acting β 2 -agonist combination treatment to triple therapy using a single inhaler. Funding Chiesi Farmaceutici SpA.

Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.

  • beclomethasone dipropionate formoterol fumarate and Glycopyrronium Bromide synergy of triple combination therapy on human airway smooth muscle ex vivo
    British Journal of Pharmacology, 2020
    Co-Authors: Paola Rogliani, Francesco Facciolo, Maria Gabriella Matera, Mario Cazzola, Luigino Calzetta
    Abstract:

    Background and purpose Combining inhaled corticosteroids (ICSs), long-acting β2 -adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is recommended to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). Clinical benefits have been demonstrated for ICS/LABA/LAMA combinations. This study characterized the interaction between the ICS beclomethasone dipropionate, the LABA formoterol fumarate and the LAMA Glycopyrronium Bromide in human airways. Experimental approach Human passively sensitized airways and bronchi from COPD donors were stimulated with histamine or carbachol. Tissues were incubated overnight with beclomethasone and then treated with formoterol and Glycopyrronium, alone or in triple combination. The interaction was assessed by using Bliss Independence and Unified Theory theorems. Key results Beclomethasone/formoterol/Glycopyrronium combination synergistically relaxed medium bronchi and small airways. Beclomethasone/formoterol/Glycopyrronium combination at 100:6:12.5 combination ratio was a balanced drug mixture leading to very strong synergistic effect on relaxation of medium bronchi (Combination Index: from 0.042 to 0.96) and middle to very strong synergy in small airways (Combination Index: from 0.018 to 0.310). The synergy was related with the activation of intracellular glucocorticoid receptors and Gsα subunit G-protein of β2 -adrenoceptors, leading to the modulation of cyclic AMP-dependent PKA pathway. Conclusion Triple beclomethasone/formoterol/Glycopyrronium combination induces synergistic bronchorelaxant effect in medium and small human airways, at least in ex vivo experiments. Further research is needed to confirm these findings in clinical studies in patients with asthma or COPD.

  • pharmacological characterisation of the interaction between Glycopyrronium Bromide and indacaterol fumarate in human isolated bronchi small airways and bronchial epithelial cells
    Respiratory Research, 2016
    Co-Authors: Mario Cazzola, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Ermanno Puxeddu, Maria Gabriella Matera
    Abstract:

    Background Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between Glycopyrronium Bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction.

  • pharmacological characterisation of the interaction between Glycopyrronium Bromide and indacaterol fumarate in human isolated bronchi small airways and bronchial epithelial cells
    Respiratory Research, 2016
    Co-Authors: Mario Cazzola, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Ermanno Puxeddu, Josuel Ora, Maria Gabriella Matera
    Abstract:

    Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between Glycopyrronium Bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction. The effects of Glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach. Glycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P   0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase. Glycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium.

  • translational study searching for synergy between Glycopyrronium and indacaterol
    COPD: Journal of Chronic Obstructive Pulmonary Disease, 2015
    Co-Authors: Mario Cazzola, Andrea Segreti, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Maria Gabriella Matera
    Abstract:

    We aimed to explore whether the acute bronchodilation induced by indacaterol 150 μg and Glycopyrronium Bromide 50 μg is additive or synergistic with respect to monocomponents by testing the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. Both indacaterol and Glycopyrronium caused a concentration-dependent relaxation of human isolated bronchial tissues sub-maximally pre-contracted with acetylcholine; Glycopyrronium was significantly more potent than indacaterol. The analysis of data using the Bliss Independence (BI) criterion indicated that Glycopyrronium plus indacaterol produced an additive interaction at the isoeffective concentrations inducing EC20 and a significant synergistic relaxant effect at isoeffective concentrations inducing EC30. In COPD patients, the inhalation of indacaterol and Glycopyrronium in combination significantly anticipated at 15 min post-administration the mean peak of bronchodilatory effect compared to the two drugs administered alone. The study of interaction between indacaterol and Glycopyrronium by BI analysis evidenced an additive effect for FEV1 between 5 min and 180 min post-inhalation, with synergistic interaction at 15 min post-administration, compared to the bronchodilation induced by these drugs administered alone. This study suggests that the combination ensures a broncholytic effect that is greater than that induced by the single monocomponents.

  • long acting muscarinic receptor antagonists for the treatment of respiratory disease
    Pulmonary Pharmacology & Therapeutics, 2013
    Co-Authors: Mario Cazzola, Clive P Page, Maria Gabriella Matera
    Abstract:

    The use of muscarinic receptor antagonists in the treatment of chronic obstructive pulmonary disease (COPD) is well established. More recently, the potential for long-acting muscarinic receptor antagonists (LAMAs) in the treatment of asthma has also been investigated. While LAMAs offer advantages over short-acting muscarinic receptor antagonists, in terms of a reduced dosing frequency, there remains a need for therapies that improve symptom control throughout both the day and night, provide better management of exacerbations and deliver improved health-related quality of life. Furthermore, the potential for unwanted anticholinergic side effects, particularly cardiovascular effects, remains a concern for this class of compounds. Novel LAMAs in clinical development for the treatment of respiratory disease include: aclidinium Bromide, NVA237 (Glycopyrronium Bromide), GP-MDI, EP-101, CHF-5259, umeclidinium Bromide, CHF-5407, TD-4208, AZD8683 and V-0162. These compounds offer potential advantages in terms of onset of action, symptom control and safety. In addition, a number of LAMAs are also being developed as combination treatments with long-acting β2-agonists (LABAs) or inhaled glucocorticosteroids, potentially important treatment options for patients who require combination therapy to achieve an optimal therapeutic response as their disease progresses. More recently, compounds such as GSK961081 and THRX-198321 have been identified that combine LAMA and LABA activity in the same molecule, and have the potential to offer the benefits of combination therapy in a single compound. Here, we review novel LAMAs and dual action compounds in clinical development, with a particular focus on how they may address the current unmet clinical needs in the treatment of respiratory disease, particularly COPD.

Luigino Calzetta - One of the best experts on this subject based on the ideXlab platform.

  • beclomethasone dipropionate formoterol fumarate and Glycopyrronium Bromide synergy of triple combination therapy on human airway smooth muscle ex vivo
    British Journal of Pharmacology, 2020
    Co-Authors: Paola Rogliani, Francesco Facciolo, Maria Gabriella Matera, Mario Cazzola, Luigino Calzetta
    Abstract:

    Background and purpose Combining inhaled corticosteroids (ICSs), long-acting β2 -adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is recommended to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). Clinical benefits have been demonstrated for ICS/LABA/LAMA combinations. This study characterized the interaction between the ICS beclomethasone dipropionate, the LABA formoterol fumarate and the LAMA Glycopyrronium Bromide in human airways. Experimental approach Human passively sensitized airways and bronchi from COPD donors were stimulated with histamine or carbachol. Tissues were incubated overnight with beclomethasone and then treated with formoterol and Glycopyrronium, alone or in triple combination. The interaction was assessed by using Bliss Independence and Unified Theory theorems. Key results Beclomethasone/formoterol/Glycopyrronium combination synergistically relaxed medium bronchi and small airways. Beclomethasone/formoterol/Glycopyrronium combination at 100:6:12.5 combination ratio was a balanced drug mixture leading to very strong synergistic effect on relaxation of medium bronchi (Combination Index: from 0.042 to 0.96) and middle to very strong synergy in small airways (Combination Index: from 0.018 to 0.310). The synergy was related with the activation of intracellular glucocorticoid receptors and Gsα subunit G-protein of β2 -adrenoceptors, leading to the modulation of cyclic AMP-dependent PKA pathway. Conclusion Triple beclomethasone/formoterol/Glycopyrronium combination induces synergistic bronchorelaxant effect in medium and small human airways, at least in ex vivo experiments. Further research is needed to confirm these findings in clinical studies in patients with asthma or COPD.

  • pharmacological characterisation of the interaction between Glycopyrronium Bromide and indacaterol fumarate in human isolated bronchi small airways and bronchial epithelial cells
    Respiratory Research, 2016
    Co-Authors: Mario Cazzola, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Ermanno Puxeddu, Maria Gabriella Matera
    Abstract:

    Background Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between Glycopyrronium Bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction.

  • pharmacological characterisation of the interaction between Glycopyrronium Bromide and indacaterol fumarate in human isolated bronchi small airways and bronchial epithelial cells
    Respiratory Research, 2016
    Co-Authors: Mario Cazzola, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Ermanno Puxeddu, Josuel Ora, Maria Gabriella Matera
    Abstract:

    Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between Glycopyrronium Bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction. The effects of Glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach. Glycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P   0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase. Glycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium.

  • translational study searching for synergy between Glycopyrronium and indacaterol
    COPD: Journal of Chronic Obstructive Pulmonary Disease, 2015
    Co-Authors: Luigino Calzetta, Andrea Segreti, Francesco Facciolo, Paola Rogliani
    Abstract:

    AbstractWe aimed to explore whether the acute bronchodilation induced by indacaterol 150 μg and Glycopyrronium Bromide 50 μg is additive or synergistic with respect to monocomponents by testing the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. Both indacaterol and Glycopyrronium caused a concentration-dependent relaxation of human isolated bronchial tissues sub-maximally pre-contracted with acetylcholine; Glycopyrronium was significantly more potent than indacaterol. The analysis of data using the Bliss Independence (BI) criterion indicated that Glycopyrronium plus indacaterol produced an additive interaction at the isoeffective concentrations inducing EC20 and a significant synergistic relaxant effect at isoeffective concentrations inducing EC30. In COPD patients, the inhalation of indacaterol and Glycopyrronium in combination significantly anticipated at 15 min post-administration the mean peak of bronchodilatory effect compared to the two drugs administered alone. ...

  • translational study searching for synergy between Glycopyrronium and indacaterol
    COPD: Journal of Chronic Obstructive Pulmonary Disease, 2015
    Co-Authors: Mario Cazzola, Andrea Segreti, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Maria Gabriella Matera
    Abstract:

    We aimed to explore whether the acute bronchodilation induced by indacaterol 150 μg and Glycopyrronium Bromide 50 μg is additive or synergistic with respect to monocomponents by testing the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. Both indacaterol and Glycopyrronium caused a concentration-dependent relaxation of human isolated bronchial tissues sub-maximally pre-contracted with acetylcholine; Glycopyrronium was significantly more potent than indacaterol. The analysis of data using the Bliss Independence (BI) criterion indicated that Glycopyrronium plus indacaterol produced an additive interaction at the isoeffective concentrations inducing EC20 and a significant synergistic relaxant effect at isoeffective concentrations inducing EC30. In COPD patients, the inhalation of indacaterol and Glycopyrronium in combination significantly anticipated at 15 min post-administration the mean peak of bronchodilatory effect compared to the two drugs administered alone. The study of interaction between indacaterol and Glycopyrronium by BI analysis evidenced an additive effect for FEV1 between 5 min and 180 min post-inhalation, with synergistic interaction at 15 min post-administration, compared to the bronchodilation induced by these drugs administered alone. This study suggests that the combination ensures a broncholytic effect that is greater than that induced by the single monocomponents.