[Where we stand with asthma: optimized medical care and biologic therapy for children]. / Le point sur l'asthme en pédiatrie : optimisation de la prise en charge et thérapies biologiques.

Asthma recommendations are in constant evolution. Salbutamol exclusivity as the historical reference treatment for asthma exacerbations is now questioned. In case of light to moderate crisis, budesonide/formoterol, combining an inhaled corticosteroid and a fast acting long lasting beta2 agonist, can now be proposed as first line as needed treatment, for adolescents older than 12 years old. In addition, progress in fundamental research revealed the heterogeneous nature of asthma and allowed for the emergence of new-targeted therapies.

La prise en charge de l'asthme est en constante évolution. L'exclusivité du salbutamol, traitement historique de référence des exacerbations aiguës, même légères, est remise en question depuis plusieurs années. En cas de symptômes ou crise légère à modérée, le budésonide/formotérol, combiné de corticostéroïde inhalé et bronchodilatateur (ß2-agoniste) d'action rapide et prolongée, peut dorénavant être proposé en première intention, à la demande, y compris en pédiatrie, notamment à partir de 12 ans. De plus, les progrès en recherche fondamentale ont permis de révéler la nature hétérogène de l'asthme et de faire émerger de nouvelles cibles thérapeutiques. En particulier, les patients asthmatiques peuvent bénéficier de l'entrée des biologiques dans l'arsenal thérapeutique.

Homeopatia: uma opção terapêutica no tratamento da asma / Homeopathy: a therapeutic option in the treatment of asthma

A asma é uma doença inflamatória crônica das vias aéreas que afeta tanto crianças quanto adultos, com alta prevalência em diversos países e incidência em adultos jovens, em ascensão no mundo ocidental. A proposta deste trabalho é analisar as evidências clínicas acerca da eficácia da homeopatia no tratamento da asma. Inicialmente, foi realizado um levantamento dos consensos atuais para diagnóstico, classificação e tratamento convencional da asma conforme as diretrizes da Sociedade Brasileira de Pneumologia e Tisiologia (SBPT) e da Global Initiative for Asthma (GINA). A seguir, foi feita uma revisão de literatura com o objetivo de analisar publicações acerca do tratamento homeopático na asma, tendo como fonte de levantamento os trabalhos publicados a partir de 2013 nas bases de dados PubMed, Scientific Electronic Library Online (SciELO) e Biblioteca Virtual de Saúde (BVS). As palavras-chaves/descritores utilizadas para a busca foram "asma" e "homeopatia". Dentro da temática proposta foram selecionados apenas três artigos e uma revisão sistemática. Somente um estudo prospectivo longitudinal recomendou o uso de tratamento homeopático juntamente com o tratamento convencional. Os resultados da revisão sistemática sugerem qualitativamente um papel definido da homeopatia além do placebo, mas devido às inadequações qualitativas e quantitativas dos trabalhos, o uso da homeopatia individualizada no tratamento da asma permanece inconclusivo. A falta de evidências nem sempre significa que o tratamento é ineficaz, mas pode evidenciar que a eficácia não foi adequadamente investigada. Pesquisas de alta qualidade, como ocorre na terapia convencional, devem ser fomentadas no tratamento homeopático da asma.

Effects of treatment with montelukast alone, budesonide/formoterol alone and a combination of both in cough variant asthma.

BACKGROUND: Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting ß2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA. METHODS: Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 µg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis. RESULTS: The median cough VAS score (median from 6.0 to 2.0 in the M group, 5.0 to 1.0 in the BF group and 6.0 to 1.0 in the MBF group, all p < 0.001), daytime CSS (all p < 0.01) and night-time CSS (all p < 0.001) decreased significantly in all three groups after treatment for 8 weeks. Meanwhile, the LogC5 and sputum Eos% improved significantly in all three groups after 8 weeks treatment (all p < 0.05). No significant differences were found in the changes of the VAS score, daytime and night-time CSSs, LogC5 and sputum Eos% among the three groups from baseline to week 8 (all p > 0.05). The BF and MBF groups also showed significant decreases in FeNO after 8 weeks treatment (p = 0.001 and p = 0.008, respectively), while no significant change was found in the M group (p = 0.457). Treatment with MBF for 8 weeks significantly improved the FEV1/FVC as well as the MMEF% pred and decreased the blood Eos% (all p < 0.05). CONCLUSIONS: Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013.

Economic Evaluation of Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate for the Treatment of Moderate to Very Severe Chronic Obstructive Pulmonary Disease in China Using a Semi-Markov Model.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease with considerable clinical and socioeconomic impact. Budesonide/glycopyrrolate/formoterol fumarate (BGF) is a newly approved pharmacotherapy for COPD in China that has been shown to improve lung function and reduce the risk of exacerbations, but the cost-effectiveness of BGF remains unknown. The objective of this study was to evaluate the cost-effectiveness of BGF in patients with moderate to very severe COPD from a Chinese healthcare system perspective. METHODS: A semi-Markov model was developed to compare the costs and benefit of treatment with BGF versus a composite comparator of long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) therapies. Clinical inputs for BGF and the composite comparator were based on the KRONOS study (NCT02497001) and a network meta-analysis. Cost inputs were derived from published literature and Chinese government documents, supplemented by expert opinion where necessary. Health-related quality-of-life inputs were also obtained based on the KRONOS study. Lifetime costs, number of exacerbations, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. Costs were measured in 2020 Chinese Yuan (CN¥) and converted into US dollars (US$). Scenario analyses and sensitivity analyses were conducted. RESULTS: Over the lifetime horizon, BGF treatment led to fewer moderate and severe exacerbations (4.01 and 0.87, respectively) versus the composite comparator (8.42 and 2.04, respectively), with a base-case ICER of CN¥13,685.94 (US$1983.47) per QALY gained. Scenario analyses considering different population and utilities resulted in ICERs ranging from dominant to CN¥13,673.91 (US$1981.73). Extensive sensitivity analyses indicated robust base-case results since all analyses yielded ICERs below the conservative cost-effectiveness threshold of one times the Chinese per capita gross domestic product (CN¥72,447.00 [US$10,499.57], 2020). CONCLUSION: Triple therapy with BGF was predicted to improve outcomes and be a cost-effective treatment option compared with LAMA/LABA therapies for patients with moderate to very severe COPD in China.

[Fixed combination of budesonide, formoterol, glycopyrronium for the treatment of severe COPD : Trixeo Aerosphere®]. / Le médicament du mois. Combinaison fixe budésonide, formotérol, glycopyronium pour le traitement de la BPCO modérée à sévère : Trixeo Aerosphère®.

Here we present pharmacological and clinical properties of a new fixed triple inhaled combination including an inhaled corticoid, a long acting ?2 agonist and a long acting anticholinergic for the treatment of severe chronic obstructive pulmonary disease (COPD). Trixeo Aerosphere® is the name of this triple combination which contains 160 µg budesonide, 4,8 µg formoterol and 9 µg glycopyrronium delivered by a pMDI. As compared to a budesonide/formoterol combination, Trixeo Aerosphere® improves forced expiratory volume in the first second (FEV1). As compared to glycopyrronium/formoterol combination, Trixeo Aerosphere® reduces exacerbation rate, improved quality of life and most importantly reduces mortality with a benefit increasing with blood eosinophil count. Trixeo Aerosphere® 320/18/9.6 is delivered twice daily 2 inhalations and is indicated in moderate to severe COPD insufficiently controlled by LABA/LAMA (long-acting ?2-adrenergic receptor agonist/ long-acting ?2-muscarinic receptor agonist) or ICS/LABA (inhaled corticosteroid/long-acting ?2-adrenergic receptor agonist).

Nous présentons dans cet article les propriétés pharmacologiques et les effets cliniques d'une nouvelle triple combinaison fixe inhalée comprenant un corticoïde inhalé, un ?2 mimétique à longue durée d'action et un anticholinergique à longue durée d'action, destinée au traitement de la bronchopneumopathie chronique obstructive (BPCO) sévère. Cette combinaison qui porte le nom de Trixeo Aerosphere® regroupe, dans le même dispositif, 160 µg de budésonide, 4,8 µg de formotérol et 18 µg de glycopyrronium. Par rapport à une combinaison budésonide/formotérol, le Trixeo Aerosphere® améliore la valeur du volume expiratoire maximum par seconde (VEMS). Par rapport à une combinaison formotérol/glycopyrronium, le Trixeo Aerosphere® réduit la fréquence des exacerbations et réduit la mortalité avec un bénéfice qui augmente avec le taux des éosinophiles circulants. Le Trixeo Aerosphere®, à la dose de 2X2 bouffées/24h, est indiqué dans le traitement des patients BPCO modérés à sévères insuffisamment contrôlés par une bithérapie LABA/LAMA (long-acting ?2-adrenergic receptor agonist/ long-acting ?2-muscarinic receptor agonist) ou ICS/LABA (inhaled corticosteroid/long-acting ?2-adrenergic receptor agonist).

How the cost-effectiveness results change in the China health policy environment: an economic evaluation of glycopyrrolate/formoterol for the treatment of COPD.

OBJECTIVE: To investigate the cost-effectiveness of glycopyrrolate/formoterol compared with tiotropium bromide for the treatment of moderate-to-severe COPD in China and discuss the influence of healthcare policies on the economic evaluation. METHODS: A Markov model with seven disease states was built to evaluate the lifetime cost-effectiveness of glycopyrrolate/formoterol from the perspective of the Chinese healthcare sector. Drug prices both before and after the negotiation were applied to discuss the influence on the economic evaluation results. Exacerbation and adverse event were included in each cycle. The improvement of forced expiratory volume in 1 second (FEV1) and incidence rate of exacerbation were derived from pooled PINNACLE analysis. Mortality rates from Chinese life tables were adjusted using hazard ratios. Direct medical costs were modeled in accordance with the perspective chosen. Health resource utilization were derived from previous studies and expert's opinions. Life-years gained, quality-adjusted life years (QALYs), and incidence of exacerbation were simulated as the health outcomes. One-way sensitivity analysis and probability analysis were conducted to explore the robustness of the base case results. Several scenario analyses were also designed. RESULTS: Glycopyrrolate/formoterol generated an additional 0.0063 LYs and 0.0032 QALYs with lower lifetime costs compared with tiotropium (CNY 27,854 vs. CNY 33,189) and was proved to be the dominant strategy in the base case analysis. The one-way sensitivity analysis confirmed the robustness of the base case results. The probabilities of glycopyrrolate/formoterol being cost-effective were 96.5, 95.7, and 93.0% when CNY 72,000 (1 time GDP per capital), CNY 108,000, and CNY 216,000 were used as thresholds, respectively. Compared with the scenario where price before negotiation was used, the cost-effectiveness based on current price was significantly increased. CONCLUSION: Glycopyrrolate/formoterol was demonstrated to be a clinically and cost-effective treatment for moderate-to-severe COPD in China using the latest price. The negotiation policy could increase the cost-effectiveness and benefit the patients.

[Anti-asthma components and mechanism of Kechuanting acupoint application therapy: based on serum metabolomics and network pharmacology].

This study aims to explore the anti-asthma components and mechanism of Kechuanting acupoint application therapy(KAAT) based on serum metabolomics and network pharmacology. A total of 60 asthma patients who had used low-dose inhaled corticosteroids-formoterol(ICS-formoterol) for a long time were randomized into the western medicine group(low-dose ICS-formoterol) and western medicine+Kechuanting group(KAAT+low-dose ICS-Formoterol), 30 in either group. In addition, 30 healthy people were included as the control(no intervention). The asthma control test(ACT) score, forced expiratory volume in 1 second(FEV1), and peak expiratory flow(PEF) were measured in the western medicine group and western medicine+Kechuanting group before and after treatment. The potential biomarkers of KAAT in the treatment of asthma were screened by gas chromatography-mass spectrometry combined with multivariate analysis, and the related metabolic pathways were further analyzed. UPLC/LTQ-Orbitrap-MS, together with network pharmacology, was employed to construct the component-target-pathway network. Thereby, the effective components and me-chanism of KAAT in the treatment of asthma were clarified. According to the ACT score, FEV1, and PEF, KAAT was effective in the treatment of asthma. A total of 10 endogenous biomarkers of KAAT in the treatment of asthma were screened by serum metabolomics, and the pathways of the metabolism of glycine, serine and threonine, and the metabolism of glyoxylic acid and dicarboxylic acid were obtained. UPLC/LTQ-Orbitrap-MS identified 51 chemical components of KAAT: 24 flavonoids, 11 alkaloids, 8 phenols, 2 diterpenoids, 2 triterpenoids, 2 glycosides, and 2 aldehydes. Network pharmacology analysis suggested that KAAT mainly acted on serum crea-tinine(SRC), matrix metalloproteinase 9(MMP-9), and other target proteins. The treatment was closely related to metabolic pathway, phosphatidylinositol 3-kinase-protein kinase B(PI3 K-Akt), mitogen-activated protein kinase(MAPK), and calcium signaling pathway. Sinapine thiocyanate, corydaline, dihydroberberine, stylopine, leonticine, N-methyl tetrahydroberberine, kaempferide, erio-dictyol, quercetin, catechin, 6-gingerol, 6-shogaol, ingenol, and luteolin may be potential effective compounds of KAAT in the treatment of asthma. This study preliminarily revealed that the effective components and mechanism of KAAT in treatment of asthma based on serum metabolomics and network pharmacology. It lays a theoretical foundation for in-depth study of the mechanism and clinical development and application.

Improvements in lung function with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler versus dual therapies in patients with COPD: a sub-study of the ETHOS trial.

BACKGROUND: In the phase III, 52-week ETHOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF), at two inhaled corticosteroid dose levels, resulted in significantly lower moderate/severe exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) and budesonide/formoterol fumarate (BFF). Here, we report results from the ETHOS pulmonary function test (PFT) sub-study, which assessed lung function in a subset of ETHOS patients. METHODS: ETHOS (NCT02465567) was a randomized, double-blind, multi-center, parallel-group study in patients with moderate to very severe COPD who had experienced ⩾1 moderate/severe exacerbation in the previous year. Patients received BGF 320/18/9.6 µg, BGF 160/18/9.6 µg, GFF 18/9.6 µg, or BFF 320/9.6 µg twice daily via a single metered dose Aerosphere inhaler for 52 weeks. A subset of patients participated in the 4-hour PFT sub-study; primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in one second (FEV1) versus GFF and FEV1 area under the curve from 0 to 4 hours (AUC0-4) versus BFF at week 24. RESULTS: The PFT modified intent-to-treat population included 3088 patients (mean age 64.4 years; mean reversibility post-albuterol 16.7%; mean post-albuterol FEV1% predicted 42.8). BGF 320/18/9.6 µg and 160/18/9.6 µg significantly improved morning pre-dose trough FEV1 at week 24 versus GFF (p ⩽ 0.0035 for both). Improvements in trough FEV1 were also observed at week 52 for BGF 320/18/9.6 µg and 160/18/9.6 µg versus GFF (p ⩽ 0.0005 for both). For FEV1 AUC0-4 at week 24, BGF 320/18/9.6 µg and 160/18/9.6 µg showed significant improvements versus BFF (p < 0.0001 for both). Improvements were maintained at week 52 (p < 0.0001). CONCLUSIONS: BGF 320/18/9.6 µg and 160/18/9.6 µg significantly improved trough FEV1versus GFF and FEV1 AUC0-4versus BFF at week 24. The lung function benefits with both doses of BGF were maintained following 52 weeks of treatment.The reviews of this paper are available via the supplemental material section.

Budesonide/Glycopyrronium/Formoterol: A Review in COPD.

Budesonide/glycopyrronium/formoterol (BREZTRI AEROSPHERE™; TRIXEO AEROSPHERE™) is an inhaled fixed-dose combination of the inhaled corticosteroid (ICS) budesonide, the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide and the long-acting ß2-agonist (LABA) formoterol fumarate approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). It is delivered via a pressurized metered-dose Aerosphere inhaler and is formulated using co-suspension delivery technology. In two pivotal phase III trials of 24-52 weeks' duration, budesonide/glycopyrronium/formoterol reduced the rates of moderate/severe COPD exacerbations and improved lung function to a greater extent than budesonide/formoterol and/or glycopyrronium/formoterol. Budesonide/glycopyrronium/formoterol also demonstrated beneficial effects on dyspnoea, rescue medication requirements and health-related quality of life (HR-QOL), and reduced the risk of all-cause mortality. Budesonide/glycopyrronium/formoterol was generally well tolerated, with the tolerability profile being generally similar to that of the individual components. Budesonide/glycopyrronium/formoterol provides a useful and convenient option for the maintenance treatment of COPD, including for patients whose disease is inadequately controlled with dual ICS/LABA or LAMA/LABA therapy.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease that is characterized by chronic airflow limitation and persistent respiratory symptoms. A step-up treatment approach combining an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA) and a long-acting ß₂-agonist (LABA) may provide clinical benefits in patients with COPD whose disease is inadequately controlled by dual therapies (ICS/LABA or LAMA/LABA). Budesonide/glycopyrronium/formoterol (BREZTRI AEROSPHERE™; TRIXEO AEROSPHERE™) is a fixed-dose ICS/LAMA/LABA combination approved for the maintenance treatment of COPD. It is administered twice daily via a single pressurized metered-dose Aerosphere inhaler. Patients with moderate to very severe COPD receiving budesonide/glycopyrronium/formoterol had fewer moderate or severe COPD exacerbations and improved lung function, respiratory symptoms and quality of life compared with patients receiving ICS/LABA or LAMA/LABA therapy. The risk of death was reduced compared with that of patients receiving LAMA/LABA therapy. Budesonide/glycopyrronium/formoterol was generally well tolerated, with similar rates of adverse events to dual therapy. Budesonide/glycopyrronium/formoterol is a useful and convenient option for the maintenance treatment of COPD.

Aclidinium bromide/formoterol fumarate as a treatment for COPD: an update.

Introduction: Aclidinium/formoterol is a long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) dual bronchodilator used as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The efficacy of aclidinium/formoterol has been demonstrated consistently in patients with moderate-to-severe COPD versus placebo and monocomponents, with a comparable safety profile.Areas covered: This review examines recent research findings that expand our understanding of the impact of aclidinium/formoterol on the burden of COPD. Reviewed outcomes include improvements in lung function, respiratory symptoms, health-related quality of life, exercise tolerance, exacerbation rates, and clinically important deteriorations. In addition, the reported cardiovascular safety of aclidinium and current LAMA/LABA treatment recommendations are discussed.Expert opinion: Aclidinium/formoterol reduces disease burden in patients with COPD, including those that are treatment-naïve, without a significant increase in safety risk compared with monotherapies. Furthermore, evidence supports an improvement in lung function over a 24-hour period with aclidinium/formoterol treatment versus monotherapy and placebo, which may offer an advantage over some once-daily LAMA/LABA combinations. In summary, the recent evidence discussed in this review adds weight to the use of LAMA/LABA combinations as an initial therapy for certain patients newly diagnosed with COPD.

Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting ß2-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting ß2-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study.

BACKGROUND: Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting ß2-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects. RESEARCH QUESTION: Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD? STUDY DESIGN AND METHODS: We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vs three commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively. RESULTS: Patients with COPD initiating IND/GLY and VI/UMEC showed an 11% (incidence rate ratio [IRR], 0.89; 95% CI, 0.80-0.98) and 20% (IRR, 0.80; 95% CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vs FF/BDP, were associated with a 27% (hazard ratio [HR], 0.73; 95% CI, 0.59-0.90) to 42% (HR, 0.58; 95% CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs. INTERPRETATION: Both LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.

Umeclidinium/Vilanterol Compared with Fluticasone Propionate/Salmeterol, Budesonide/Formoterol, and Tiotropium as Initial Maintenance Therapy in Patients with COPD Who Have High Costs and Comorbidities.

BACKGROUND: Comorbidities in patients with chronic obstructive pulmonary disease (COPD) are associated with increased medical costs and risk of exacerbations. This study compared COPD-related medical costs and exacerbations in high-cost, high-comorbidity patients with COPD receiving initial maintenance treatment (IMT) with umeclidinium/vilanterol (UMEC/VI) versus fluticasone propionate/salmeterol (FP/SAL), budesonide/formoterol (B/F), or tiotropium (TIO). METHODS: This retrospective, matched cohort study identified patients from Optum's de-identified Clinformatics Data Mart database who initiated UMEC/VI, FP/SAL, B/F, or TIO between January 1, 2014 and December 31, 2018 (index date defined as date of the first fill). Eligibility criteria included age ≥40 years at index, ≥1 pre-index COPD diagnosis, no pre-index asthma diagnosis, 12 months of continuous insurance coverage pre-index, and high pre-index costs (≥80th percentile of IMT population) and comorbidities (Quan-Charlson comorbidity index ≥3). Propensity score matching was used to control for potential confounders. On-treatment COPD-related medical costs (primary endpoint) and exacerbations were evaluated. RESULTS: Matched cohorts were well balanced on baseline characteristics (UMEC/VI vs FP/SAL: n=1194 each; UMEC/VI vs B/F: n=1441 each; UMEC/VI vs TIO: n=1277 each). Patients receiving UMEC/VI had significantly lower COPD-related medical costs versus FP/SAL (difference: $6587 per patient per year; P=0.048), and numerically lower costs versus B/F and TIO. Patients initiating UMEC/VI had significantly lower risk of COPD-related severe exacerbation versus FP/SAL (hazard ratio [95% CI]: 0.78 [0.62, 0.98]; P=0.032), B/F (0.77 [0.63, 0.95]; P=0.016), and TIO (0.79 [0.64, 0.98]; P=0.028). The rate of COPD-related severe exacerbations was significantly lower with UMEC/VI versus FP/SAL (rate ratio [95% CI]: 0.73 [0.59, 0.91]; P=0.008) and B/F (0.73 [0.59, 0.93]; P=0.012), and numerically lower versus TIO (0.83 [0.68, 1.04]; P=0.080). CONCLUSION: These findings suggest that high-cost, high-comorbidity patients with COPD receiving UMEC/VI compared with FP/SAL, B/F, and TIO as IMT may have lower medical costs and exacerbation risk.

Efficacy and safety of triple combination therapy for treating chronic obstructive pulmonary disease: an expert review.

Introduction: The current recommendations of chronic obstructive pulmonary disease (COPD) suggest to escalate from inhaled corticosteroid/long-acting ß2-adrenoceptor agonist (ICS/LABA) treatment to triple therapy in patients experiencing persistent breathlessness, exercise limitation, or exacerbation. The addition of an ICS to LABA/long-acting muscarinic antagonist (LAMA) combination is recommended for frequently exacerbating patients with high levels of blood eosinophils. Nowadays, three triple therapies have been approved as fixed-dose combinations (FDCs) for the treatment of COPD: beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FOR/GLY), fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), and budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR).Areas covered: This narrative review evaluates the efficacy and safety profile of triple FDC therapy for the treatment of COPD, by evaluating the data originating from pivotal randomized-controlled trials (RCTs).Expert opinion: The currently approved triple FDCs exert a protective effect against the risk of COPD exacerbation compared to ICS/LABA and LABA/LAMA, with some concerns regarding the risk of pneumonia for some specific FDCs. Since the assessed RCTs were characterized by important confounders, the obtained results should be interpreted with caution. Indeed, FDCs provide advantages in terms of improved adherence to treatment and lower errors in COPD management; however, direct head-to-head comparisons are needed to establish real differences between the currently approved triple FDCs.

Glycopyrrolate and formoterol fumarate for the treatment of COPD.

INTRODUCTION: Long acting bronchodilators are nowadays the central treatment for management of stable COPD. Several combinations exist within the market with different formulation devices. This article reviews a recent dual combination of glycopyrronium and formoterol fumarate in an innovative pMDI-fixed dual combination, Bevespi® Aerosphere. AREAS COVERED: This article explored the literature to understand the place of this novel combination and unique delivery drug device in today's therapeutic arsenal. Clinical efficacy and safety have been evaluated through the different clinical trials published in public databases. EXPERT OPINION: Within the fixed-dose combinations, Glycopyrrolate and formoterol fumarate offer a credible unique pMDI option to be given twice a day. LABA-LAMA offers an ICS-free alternative in COPD pharmacology which represents an important treatment option given the current debate over whether or not, maintenance triple therapy combined with ICS are benefic in the long term.

Airway Deposition of Extrafine Inhaled Triple Therapy in Patients with COPD: A Model Approach Based on Functional Respiratory Imaging Computer Simulations.

Introduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting ß2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs. Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients' high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition. Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were <1, indicating greater peripheral than central deposition (0.48±0.13, 0.48±0.13 and 0.49±0.13 for BDP, FF and GB, respectively; 1.96±0.84, 0.97±0.34 and 1.20±0.48 for FluF, VI and UMEC, respectively). Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB.

Effectiveness and Tolerability of LABA/LAMA Fixed-Dose Combinations Aclidinium/Formoterol, Glycopyrronium/Indacaterol and Umeclidinium/Vilanterol in the Treatment of COPD in Daily Practice - Results of the Non-Interventional DETECT Study.

Background: LABA (long-acting ß2-agonists) and/or LAMA (long-acting muscarinic antagonists) represent the first treatment options for patients with symptomatic COPD. Although both display different mechanisms of activity, in combination they have a stronger broncho-dilating effect than monotherapy; hence, a combination of both LABA and LAMA is particularly recommended for patients whose symptoms cannot be sufficiently improved by a single active ingredient. To date, only few data have been collected regarding the therapeutic outcomes of approved LABA/LAMA fixed-dose combinations (FDCs) under everyday (real-life) conditions in non-clinical trial settings. Objective and Methods: The main objective of the DETECT study was to investigate the impact of aclidinium/formoterol (AB/FF, b.i.d.), glycopyrronium/indacaterol (GLY/IND, q.d.) and umeclidinium/vilanterol (UME/VL, q.d.) in patients with COPD in daily clinical practice. Therefore, a prospective, non-randomized, 12-month, observational study was implemented to assess the effectiveness of these treatments in patients who had been switched to FDC within the last 3 months or for whom such a changeover was intended. Changes in lung function were analyzed by the forced expiratory volume (FEV1) and forced vital capacity (FVC) measures. Quality of life and well-being were evaluated by the COPD Assessment Test (CAT™). Furthermore, a number of exacerbations and early morning COPD symptoms were documented. Results: In total, 3653 patients were enrolled. FEV1 and FVC values significantly improved during the study with AB/FF (increase by 0.09 ± 0.40 L and 0.10 ± 0.57 L, respectively; p<0.0001), GLY/IND (0.06±0.38/0.05±0.51 L; p<0.0001 and p=0.0025) and UME/VL (0.12±0.39/0.10±0.52 L; p<0.0001). CAT scores decreased indicating improved COPD (AB/FF, 4.17±8.30; GLY/IND, 3.66±7.88; UME/VL, 4.06±7.96; p<0.0001). Moreover, the number of exacerbations as well as early morning COPD symptoms similarly diminished in all treatment groups. A comparable proportion of patients with adverse drug reactions was recorded: AB/FF, 4.07% of patients; GLY/IND, 3.52%; UME/VL, 3.64%. Conclusion: In summary, AB/FF, GLY/IND and UME/VL provided clinical benefits in lung function, quality of life and early morning COPD symptoms in a broad cohort of COPD patients under routine medical practice conditions. All three treatments were well tolerated.

Efficacy of Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhaler (BGF MDI) Versus Other Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting ß2-Agonist (ICS/LAMA/LABA) Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

INTRODUCTION: Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA). METHODS: A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St. George's Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12-24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. RESULTS: Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario. CONCLUSION: This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.

New Perspectives for Mucolytic, Anti-inflammatory and Adjunctive Therapy with 1,8-Cineole in COPD and Asthma: Review on the New Therapeutic Approach.

The mucolytic monoterpene 1,8-cineole (eucalyptol), the major constituent of eucalyptus species, is well known for its anti-inflammatory, antioxidant, bronchodilatory, antiviral and antimicrobial effects. The main protective antiviral, anti-inflammatory and mucolytic mechanisms of 1,8-cineole are the induction of interferon regulatory factor 3 (IRF3), the control of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) along with decreasing mucin genes (MUC2, MUC19). In normal human monocytes direct inhibition was shown of reactive oxygen species (ROS)-mediated mucus hypersecretion and of steroid resistence inducing superoxides (O2·-) and pro-inflammatory hydrogen peroxides (H2O2) with partial control of superoxide dismutase (SOD), which enzymatically metabolizes O2·- into H2O2. By inhibition of NF-κB, 1,8-cineole, at relevant plasma concentrations (1.5 µg/ml), strongly and significantly inhibited in normal human monocyte lipopolysaccharide (LPS)-stimulated cytokines relevant for exacerbation (tumour necrosis factor alpha (TNFα), interleukin (IL)-1ß and systemic inflammation (IL-6, IL-8). Infectious agents and environmental noxa have access via TNFα and IL-1ß to the immune system with induction of bronchitis complaints and exacerbations of chronic obstructive pulmonary disease (COPD), asthma and asthma-COPD overlap. In lymphocytes from healthy human donors 1,8-cineole inhibited TNFα, IL-1ß, IL-4 and IL-5 and demonstrated for the first time control of Th1/2-type inflammation. 1,8-Cineole at relevant plasma levels increased additively in vitro the efficacy of inhaled guideline medications of budesonide (BUD) and budesonide + formoterol ,and preliminary data also showed increased efficacy of long-acting muscarinic receptor antagonist (LAMA)-mediated cytokine inhibition in vitro. On the basis of the preclinical data, earlier randomised controlled studies with adjunctive therapy of 1,8-cineole (3 × 200 mg/day) for 6 months showed improvement of uncontrolled asthma by significant improvement of lung function, nocturnal asthma and quality of life scores and in COPD decrease of exacerbations (- 38.5%) (during wintertime). This review reports an update with reference to the literature of 1,8-cineole, also as adjunctive therapy, as a therapeutic agent for the protection and control of inflammatory airway diseases.

Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4. Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study. Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all P≤0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group. Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.

Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide: Synergy of triple combination therapy on human airway smooth muscle ex vivo.

BACKGROUND AND PURPOSE: Combining inhaled corticosteroids (ICSs), long-acting ß2 -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 ß2 -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.