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Dave Singh - One of the best experts on this subject based on the ideXlab platform.
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acute cardiovascular safety of two formulations of Beclometasone Dipropionate formoterol fumarate in copd patients a single dose randomised placebo controlled crossover study
Pulmonary Pharmacology & Therapeutics, 2017Co-Authors: Dave Singh, A Muraro, Giorgia Ciurlia, Annalisa Piccinno, Maria Bocchi, Mario ScuriAbstract:Abstract Introduction An extrafine combination of Beclometasone Dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo. Methods Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40–75 years; moderate to severe COPD (post-bronchodilator FEV 1 40–80% predicted, FEV 1 /FVC Primary objective: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR 0–4h ) at each dose level. Secondary variables included: HR 0–12h , HR peak and individual timepoint; QTcF interval; SBP and DBP AUC 0–12h ; and potassium and glucose AUC 0–4h . Adverse events (AEs) were collected. Results Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (−0.2 bpm [95% CI –1.3, 0.9] for 200/12 μg and 0.6 bpm [−0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo. Conclusions Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.
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Acute cardiovascular safety of two formulations of Beclometasone Dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study.
Pulmonary Pharmacology & Therapeutics, 2017Co-Authors: Dave Singh, A Muraro, Giorgia Ciurlia, Annalisa Piccinno, Maria Bocchi, Mario ScuriAbstract:Abstract Introduction An extrafine combination of Beclometasone Dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo. Methods Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40–75 years; moderate to severe COPD (post-bronchodilator FEV 1 40–80% predicted, FEV 1 /FVC Primary objective: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR 0–4h ) at each dose level. Secondary variables included: HR 0–12h , HR peak and individual timepoint; QTcF interval; SBP and DBP AUC 0–12h ; and potassium and glucose AUC 0–4h . Adverse events (AEs) were collected. Results Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (−0.2 bpm [95% CI –1.3, 0.9] for 200/12 μg and 0.6 bpm [−0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo. Conclusions Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.
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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, 2016Co-Authors: Dave Singh, Massimo Corradi, Mario Scuri, Alberto Papi, I Montagna, Stefano Vezzoli, G. Cohuet, Ilona Pavlisova, Catherine Francisco, Jorgen VestboAbstract: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.
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The bronchodilator effects of extrafine glycopyrronium added to combination treatment with Beclometasone Dipropionate plus formoterol in COPD: A randomised crossover study (the TRIDENT study).
Respiratory Medicine, 2016Co-Authors: Dave Singh, Stefano Petruzzelli, Winfried Schröder-babo, G. Cohuet, A Muraro, Françoise Bonnet-gonod, Martin Hoffmann, Zenon SiergiejkoAbstract:Abstract This multicentre, double-blind, randomised, placebo-controlled, crossover study aimed to determine the dose-response of the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) when added to Beclometasone Dipropionate plus formoterol fumarate (BDP/FF) in patients with COPD. Patients received extrafine GB 12.5, 25 or 50 μg twice daily (BID) or placebo for 7 days via pressurised metered dose inhaler (pMDI), and extrafine BDP/FF via pMDI throughout the study. The primary objective was to demonstrate superiority of GB plus BDP/FF versus BDP/FF in terms of FEV 1 area under the curve from 0 to 12 h (AUC 0–12h ) on Day 7. Secondary endpoints included: FEV 1 AUC 0–12h on Day 1; peak FEV 1 and FVC on Days 1 and 7; and trough (12 h post-dose) FEV 1 , FVC and inspiratory capacity (IC) on Days 1 and 7. Of 178 patients randomised (mean age 62.7 years, post-bronchodilator FEV 1 48.9%), 172 (96.6%) completed. Mean FEV 1 AUC 0–12h on Day 7 was significantly higher (p This study confirms the value of adding GB to BDP/FF to improve lung function in COPD patients. The dose of extrafine GB 25 μg BID was associated with the best efficacy/safety profile. Trial registered at ClinicalTrials.gov. Registration number NCT01476813.
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The systemic exposure to inhaled Beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size.
Pulmonary Pharmacology & Therapeutics, 2014Co-Authors: Mirco Govoni, Gianluigi Poli, Daniela Acerbi, Piotr Kuna, Dave Singh, Germano Lucci, Annalisa Piccinno, Bo L. Chawes, Roberta Baronio, Hans BisgaardAbstract:BACKGROUND: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of Beclometasone-Dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults. METHODS: The pharmacokinetics of formoterol and Beclometasone-17-monopropionate (active metabolite of Beclometasone-Dipropionate) was evaluated over 8�h from three studies, each performed in a different age and body size group. Children (7-11 years, n�=�20), adolescents (12-17 years, n�=�29) and adults (?18 years, n�=�24) received a single dose of Beclometasone/formoterol (children: 200�?g/24�?g, adolescents and adults: 400�?g/24�?g) via pMDI with AeroChamber Plus?. RESULTS: The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for Beclometasone-17-monopropionate in accordance with the halved dose of Beclometasone administered in children (90% CIs within 0.8-1.25 for formoterol and 0.4-0.625 for Beclometasone-17-monopropionate). The systemic exposure to Beclometasone-17-monopropionate and formoterol was equivalent between adolescents and adults. CONCLUSIONS: The systemic exposure to the active ingredients of a fixed dose combination of Beclometasone/formoterol administered via pMDI with AeroChamber Plus? correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.
Daniela Acerbi - One of the best experts on this subject based on the ideXlab platform.
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a two period open label single dose crossover study in healthy volunteers to evaluate the drug drug interaction between cimetidine and inhaled extrafine chf 5993
European Journal of Drug Metabolism and Pharmacokinetics, 2017Co-Authors: Fabrizia Mariotti, A Muraro, Giorgia Ciurlia, Luca Spaccapelo, Daniela AcerbiAbstract:Background and Objectives CHF 5993 is an extrafine ‘triple therapy’ combination of the long-acting muscarinic antagonist glycopyrronium bromide (GB), the long-acting β2-agonist formoterol fumarate (FF), and the inhaled corticosteroid Beclometasone Dipropionate (BDP). It is in development for chronic obstructive pulmonary disease and asthma delivered via pressurised metered-dose inhaler.
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Letter to the Editors
2015Co-Authors: Nasim Sam, Daniela Acerbi, Hans BisgaardAbstract:A clinical pharmacology study of fixed vs. free combination of inhaled Beclometasone Dipropionate and formoterol fumarate dry powder inhalers in asthmatic adolescent
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pharmacokinetics and pharmacodynamics of an extrafine fixed pmdi combination of Beclometasone Dipropionate formoterol fumarate in adolescent asthma
British Journal of Clinical Pharmacology, 2015Co-Authors: Piotr Kuna, Mario Scuri, Daniela Acerbi, Mirco Govoni, Germano Lucci, Iwona StelmachAbstract:Aim The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of Beclometasone Dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma. Methods This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 µg and 24 µg, for each treatment, respectively. Assessments were performed over 8 hours. Results In adolescents, the 90% confidence intervals (CIs) for the systemic exposure (AUC(0,t)) geometric mean ratio of the fixed combination with or without VHC vs. the free combination were within the bioequivalence range 0.80–1.25, both for Beclometasone-17-monopropionate (B17MP, the active metabolite of BDP) and formoterol. Pharmacodynamic variables for plasma potassium and glucose, pulse rate and pulmonary function in adolescents were equivalent between treatments, 95% CI within 0.9, 1.09. The upper level of 90% CIs for AUC(0,t) geometric mean ratio adolescents : adults of B17MP and formoterol after treatment with BDP/FF pMDI was lower than 1.25, 90% CI 0.78, 1.04 and 0.86, 1.17, respectively. Conclusions In adolescents the pharmacodynamics and the overall systemic exposure to the active ingredients of an extrafine fixed combination of BDP/FF pMDI with or without a VHC was equivalent to that of a free licenced combination of pMDIs of established safety and efficacy profiles. The systemic exposure in adolescents was not higher than in adults. These results support the indication for use of inhaled corticosteroid/long acting β2-adrenoceptor agonist pMDIs in adolescents at the same dosage as in adults.
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Pharmacokinetics and pharmacodynamics of an extrafine fixed pMDI combination of Beclometasone Dipropionate/formoterol fumarate in adolescent asthma.
British Journal of Clinical Pharmacology, 2015Co-Authors: Piotr Kuna, Mario Scuri, Daniela Acerbi, Mirco Govoni, Germano Lucci, Iwona StelmachAbstract:Aim The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of Beclometasone Dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma. Methods This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 µg and 24 µg, for each treatment, respectively. Assessments were performed over 8 hours. Results In adolescents, the 90% confidence intervals (CIs) for the systemic exposure (AUC(0,t)) geometric mean ratio of the fixed combination with or without VHC vs. the free combination were within the bioequivalence range 0.80–1.25, both for Beclometasone-17-monopropionate (B17MP, the active metabolite of BDP) and formoterol. Pharmacodynamic variables for plasma potassium and glucose, pulse rate and pulmonary function in adolescents were equivalent between treatments, 95% CI within 0.9, 1.09. The upper level of 90% CIs for AUC(0,t) geometric mean ratio adolescents : adults of B17MP and formoterol after treatment with BDP/FF pMDI was lower than 1.25, 90% CI 0.78, 1.04 and 0.86, 1.17, respectively. Conclusions In adolescents the pharmacodynamics and the overall systemic exposure to the active ingredients of an extrafine fixed combination of BDP/FF pMDI with or without a VHC was equivalent to that of a free licenced combination of pMDIs of established safety and efficacy profiles. The systemic exposure in adolescents was not higher than in adults. These results support the indication for use of inhaled corticosteroid/long acting β2-adrenoceptor agonist pMDIs in adolescents at the same dosage as in adults.
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The systemic exposure to inhaled Beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size.
Pulmonary Pharmacology & Therapeutics, 2014Co-Authors: Mirco Govoni, Gianluigi Poli, Daniela Acerbi, Piotr Kuna, Dave Singh, Germano Lucci, Annalisa Piccinno, Bo L. Chawes, Roberta Baronio, Hans BisgaardAbstract:BACKGROUND: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of Beclometasone-Dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults. METHODS: The pharmacokinetics of formoterol and Beclometasone-17-monopropionate (active metabolite of Beclometasone-Dipropionate) was evaluated over 8�h from three studies, each performed in a different age and body size group. Children (7-11 years, n�=�20), adolescents (12-17 years, n�=�29) and adults (?18 years, n�=�24) received a single dose of Beclometasone/formoterol (children: 200�?g/24�?g, adolescents and adults: 400�?g/24�?g) via pMDI with AeroChamber Plus?. RESULTS: The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for Beclometasone-17-monopropionate in accordance with the halved dose of Beclometasone administered in children (90% CIs within 0.8-1.25 for formoterol and 0.4-0.625 for Beclometasone-17-monopropionate). The systemic exposure to Beclometasone-17-monopropionate and formoterol was equivalent between adolescents and adults. CONCLUSIONS: The systemic exposure to the active ingredients of a fixed dose combination of Beclometasone/formoterol administered via pMDI with AeroChamber Plus? correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.
Mario Scuri - One of the best experts on this subject based on the ideXlab platform.
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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, 2017Co-Authors: Mario Scuri, Massimo Corradi, Alberto Papi, I Montagna, Stefano Vezzoli, G. Cohuet, A Muraro, David Singh, C Francisco, Stefano PetruzzelliAbstract: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.
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acute cardiovascular safety of two formulations of Beclometasone Dipropionate formoterol fumarate in copd patients a single dose randomised placebo controlled crossover study
Pulmonary Pharmacology & Therapeutics, 2017Co-Authors: Dave Singh, A Muraro, Giorgia Ciurlia, Annalisa Piccinno, Maria Bocchi, Mario ScuriAbstract:Abstract Introduction An extrafine combination of Beclometasone Dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo. Methods Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40–75 years; moderate to severe COPD (post-bronchodilator FEV 1 40–80% predicted, FEV 1 /FVC Primary objective: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR 0–4h ) at each dose level. Secondary variables included: HR 0–12h , HR peak and individual timepoint; QTcF interval; SBP and DBP AUC 0–12h ; and potassium and glucose AUC 0–4h . Adverse events (AEs) were collected. Results Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (−0.2 bpm [95% CI –1.3, 0.9] for 200/12 μg and 0.6 bpm [−0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo. Conclusions Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.
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Acute cardiovascular safety of two formulations of Beclometasone Dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study.
Pulmonary Pharmacology & Therapeutics, 2017Co-Authors: Dave Singh, A Muraro, Giorgia Ciurlia, Annalisa Piccinno, Maria Bocchi, Mario ScuriAbstract:Abstract Introduction An extrafine combination of Beclometasone Dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo. Methods Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40–75 years; moderate to severe COPD (post-bronchodilator FEV 1 40–80% predicted, FEV 1 /FVC Primary objective: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR 0–4h ) at each dose level. Secondary variables included: HR 0–12h , HR peak and individual timepoint; QTcF interval; SBP and DBP AUC 0–12h ; and potassium and glucose AUC 0–4h . Adverse events (AEs) were collected. Results Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (−0.2 bpm [95% CI –1.3, 0.9] for 200/12 μg and 0.6 bpm [−0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo. Conclusions Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.
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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, 2016Co-Authors: Dave Singh, Massimo Corradi, Mario Scuri, Alberto Papi, I Montagna, Stefano Vezzoli, G. Cohuet, Ilona Pavlisova, Catherine Francisco, Jorgen VestboAbstract: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.
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Inhaled Beclometasone Dipropionate/formoterol fumarate extrafine fixed combination for the treatment of asthma
Expert Review of Respiratory Medicine, 2016Co-Authors: Ernesto Crisafulli, Gianluigi Poli, Andrea Zanini, Giovanna Pisi, Patrizia Pignatti, Mario Scuri, Alfredo ChettaAbstract:Inhaled therapy is often considered the cornerstone of asthma management and international guidelines recommend combination therapy of inhaled corticosteroids (ICS) and long-acting-beta2-agonists (LABA) in a large proportion of asthmatic patients. The effectiveness of ICS/LABA is dependent on the correct choice of device and proper inhalation technique, this influences drug delivery and distribution along the bronchial tree, including the most peripheral airways. The fixed combination of Beclometasone Dipropionate/formoterol fumarate (BDP/FF) is the only extrafine formulation available in pressurized metered dose inhaler (pMDI) and in dry powder inhaler (DPI). Here, we focus on the recent significant advances regarding BDP/FF fixed combination for the treatment of asthma.
Gianluigi Poli - One of the best experts on this subject based on the ideXlab platform.
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Lung Deposition of the Dry Powder Fixed Combination Beclometasone Dipropionate Plus Formoterol Fumarate Using NEXThaler® Device in Healthy Subjects, Asthmatic Patients, and COPD Patients.
Journal of Aerosol Medicine and Pulmonary Drug Delivery, 2018Co-Authors: Johann Christian Virchow, Gianluigi Poli, Christiane Herpich, Claudius Kietzig, Hilke Ehlich, Daniela Braeutigam, Knut Sommerer, Sabine Häussermann, Fabrizia MariottiAbstract:Abstract Background: This study evaluated the lung deposition and the distribution pattern in the airways of a fixed combination of Beclometasone Dipropionate (BDP) and formoterol fumarate (FF) (10...
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Inhaled Beclometasone Dipropionate/formoterol fumarate extrafine fixed combination for the treatment of asthma
Expert Review of Respiratory Medicine, 2016Co-Authors: Ernesto Crisafulli, Gianluigi Poli, Andrea Zanini, Giovanna Pisi, Patrizia Pignatti, Mario Scuri, Alfredo ChettaAbstract:Inhaled therapy is often considered the cornerstone of asthma management and international guidelines recommend combination therapy of inhaled corticosteroids (ICS) and long-acting-beta2-agonists (LABA) in a large proportion of asthmatic patients. The effectiveness of ICS/LABA is dependent on the correct choice of device and proper inhalation technique, this influences drug delivery and distribution along the bronchial tree, including the most peripheral airways. The fixed combination of Beclometasone Dipropionate/formoterol fumarate (BDP/FF) is the only extrafine formulation available in pressurized metered dose inhaler (pMDI) and in dry powder inhaler (DPI). Here, we focus on the recent significant advances regarding BDP/FF fixed combination for the treatment of asthma.
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inhaled Beclometasone Dipropionate formoterol fumarate extrafine fixed combination for the treatment of asthma
Expert Review of Respiratory Medicine, 2016Co-Authors: Ernesto Crisafulli, Gianluigi Poli, Andrea Zanini, Giovanna Pisi, Patrizia Pignatti, Mario Scuri, Alfredo ChettaAbstract:Inhaled therapy is often considered the cornerstone of asthma management and international guidelines recommend combination therapy of inhaled corticosteroids (ICS) and long-acting-beta2-agonists (LABA) in a large proportion of asthmatic patients. The effectiveness of ICS/LABA is dependent on the correct choice of device and proper inhalation technique, this influences drug delivery and distribution along the bronchial tree, including the most peripheral airways. The fixed combination of Beclometasone Dipropionate/formoterol fumarate (BDP/FF) is the only extrafine formulation available in pressurized metered dose inhaler (pMDI) and in dry powder inhaler (DPI). Here, we focus on the recent significant advances regarding BDP/FF fixed combination for the treatment of asthma.
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The systemic exposure to inhaled Beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size.
Pulmonary Pharmacology & Therapeutics, 2014Co-Authors: Mirco Govoni, Gianluigi Poli, Daniela Acerbi, Piotr Kuna, Dave Singh, Germano Lucci, Annalisa Piccinno, Bo L. Chawes, Roberta Baronio, Hans BisgaardAbstract:BACKGROUND: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of Beclometasone-Dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults. METHODS: The pharmacokinetics of formoterol and Beclometasone-17-monopropionate (active metabolite of Beclometasone-Dipropionate) was evaluated over 8�h from three studies, each performed in a different age and body size group. Children (7-11 years, n�=�20), adolescents (12-17 years, n�=�29) and adults (?18 years, n�=�24) received a single dose of Beclometasone/formoterol (children: 200�?g/24�?g, adolescents and adults: 400�?g/24�?g) via pMDI with AeroChamber Plus?. RESULTS: The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for Beclometasone-17-monopropionate in accordance with the halved dose of Beclometasone administered in children (90% CIs within 0.8-1.25 for formoterol and 0.4-0.625 for Beclometasone-17-monopropionate). The systemic exposure to Beclometasone-17-monopropionate and formoterol was equivalent between adolescents and adults. CONCLUSIONS: The systemic exposure to the active ingredients of a fixed dose combination of Beclometasone/formoterol administered via pMDI with AeroChamber Plus? correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.
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Systemic exposure and implications for lung deposition with an extra-fine hydrofluoroalkane Beclometasone Dipropionate/formoterol fixed combination.
Clinical Pharmacokinectics, 2012Co-Authors: Jean Bousquet, Gianluigi Poli, Daniela Acerbi, Raffaella Monno, Steven Ramael, Fabrice NollevauxAbstract:Background and objectives Foster™ is a fixed combination of Beclometasone Dipropionate/formoterol (BDP/F). It is formulated as an extra-fine solution and delivered via a pressurized metered-dose inhaler (pMDI) using a hydrofluoroalkane (HFA) propellant. The aims of this study were to compare the systemic exposure to BDP, to its active metabolite Beclometasone-17-monopropionate (B17MP) and to formoterol after administration of BDP/F versus separate administration of a chlorofluorocarbon (CFC) formulation of BDP and formoterol HFA, and to explore a possible relationship between pharmacokinetic and pharmacodynamic findings.
Massimo Corradi - One of the best experts on this subject based on the ideXlab platform.
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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, 2017Co-Authors: Mario Scuri, Massimo Corradi, Alberto Papi, I Montagna, Stefano Vezzoli, G. Cohuet, A Muraro, David Singh, C Francisco, Stefano PetruzzelliAbstract: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.
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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, 2016Co-Authors: Dave Singh, Massimo Corradi, Mario Scuri, Alberto Papi, I Montagna, Stefano Vezzoli, G. Cohuet, Ilona Pavlisova, Catherine Francisco, Jorgen VestboAbstract: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.
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high dose Beclometasone Dipropionate formoterol fumarate in fixed dose combination for the treatment of asthma
Therapeutic Advances in Respiratory Disease, 2016Co-Authors: Massimo Corradi, Monica Spinola, Stefano Petruzzelli, Piotr KunaAbstract:The high-strength formulation of extrafine Beclometasone Dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid treatment, without increasing the dose of the bronchodilator, in patients who are not controlled with previous therapies. Two clinical studies have evaluated efficacy of high-strength BDP/Form as compared with another high-dose fixed combination and BDP monotherapy. Overall, data show that BDP/Form 200/6 μg improves lung function and has beneficial effects on symptoms, use of rescue medication and asthma control, with an acceptable safety profile comparable with that of high-dose fluticasone propionate/salmeterol. Therefore, BDP/Form 200/6 μg could be considered as an effective and safe treatment for patients with asthma who are not adequately controlled with high doses of inhaled corticosteroid monotherapy or medium doses of inhaled corticosteroid/long-acting β2-agonist combinations.
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High-dose Beclometasone Dipropionate/formoterol fumarate in fixed-dose combination for the treatment of asthma:
Therapeutic Advances in Respiratory Disease, 2016Co-Authors: Massimo Corradi, Monica Spinola, Stefano Petruzzelli, Piotr KunaAbstract:The high-strength formulation of extrafine Beclometasone Dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid treatment, without increasing the dose of the bronchodilator, in patients who are not controlled with previous therapies. Two clinical studies have evaluated efficacy of high-strength BDP/Form as compared with another high-dose fixed combination and BDP monotherapy. Overall, data show that BDP/Form 200/6 μg improves lung function and has beneficial effects on symptoms, use of rescue medication and asthma control, with an acceptable safety profile comparable with that of high-dose fluticasone propionate/salmeterol. Therefore, BDP/Form 200/6 μg could be considered as an effective and safe treatment for patients with asthma who are not adequately controlled with high doses of inhaled corticosteroid monotherapy or medium doses of inhaled corticosteroid/long-acting β2-agonist combinations.
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nexthaler an innovative dry powder inhaler delivering an extrafine fixed combination of Beclometasone and formoterol to treat large and small airways in asthma
Expert Opinion on Drug Delivery, 2014Co-Authors: Massimo Corradi, Henry Chrystyn, Borja G Cosio, Michal Pirozynski, Stelios Loukides, Monica Spinola, Renaud Louis, Omar S. UsmaniAbstract:Introduction: Airway inflammation and remodelling in asthma occur in the large airways and also in the small airways. The small airways are those < 2 mm in diameter and are significant sites of chronic asthmatic inflammation. It is important, therefore, to target the small as well as the large airways in any strategy for effective treatment of this disease.Areas covered: The present review deals with the recently developed fixed dose drug combination of Beclometasone Dipropionate/formoterol fumarate that emits extrafine particles when delivered from an innovative dry powder inhaler (DPI), NEXThaler®. The aim is to present the technical and clinical aspects of aerosolized drug delivery to the lungs.Expert opinion: The data show that the NEXThaler DPI is an efficient device for the management of persistent asthma. The evaluation of the inhalation profiles through the NEXThaler DPI demonstrates that device activation and consistent dose delivery occurs at patient achievable inhalation flow rates, and support...
