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In an open-label, randomized trial conducted in 75 general practices, once-daily treatment for chronic obstructive pulmonary disease with inhaled fluticasone furoate–vilanterol was associated with a lower rate of moderate or severe exacerbations than usual care. Guidelines on the management of chronic obstructive pulmonary disease (COPD) are based on numerous randomized, controlled trials of efficacy, which are usually generated for registration purposes. 1 However, these trials have included patients who were selected with the use of strict criteria and were closely monitored, and therefore the results have limited relevance to everyday clinical practice. 2 To counter this, it has been proposed that integrated comparative effectiveness trials involve more representative patients and be conducted in much less restricted environments. 3 – 5 The Salford Lung Study was designed to evaluate the effectiveness and safety of the once-daily inhaled combination of fluticasone . . .

The elimination of chlorinated organics (chlorobenzene as a model) in a SCR convertor has been given an increasing demand. Herein, a novel catalyst by loading CeO.sub.2 clusters on [alpha]-MnO.sub.2 nanorods has been designed for simultaneous abatement of NO.sub.x and chlorobenzene. The CeO.sub.2 modification provided new active center for CB oxidation as well as promoted the SCR activity of MnO.sub.2 by increasing both redox performance and adsorption property. The independent effect of dual active centers can be inferred from changing the amount of CeO.sub.2 content and atmosphere. In this regard, structure and chemical characterizations were conducted to further reveal the interaction mechanism and function in specific reaction.

Background Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler. Methods Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM ® . Results The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/ F ) with FF CL/ F 35% lower in patients of Japanese heritage across all treatments and FF CL/ F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/ F and weight on apparent volume of distribution (V2/ F ) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/ F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/ F and approximately an 8% increase in UMEC V2/ F . For a subject with COPD who smoked, UMEC CL/ F was 28% higher. For VI, weight on CL/ F and smoking status on V2/ F with an approximately 4% increase in VI CL/ F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/ F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment. Conclusions All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Background Combination therapy with an inhaled corticosteroid (ICS) and long-acting β2 agonist (LABA) is recommended for patients with asthma symptomatic on ICS alone. However, there is ongoing debate regarding the risk-benefit ratio of using LABA in asthma. Objective To evaluate the effect of the addition of a novel LABA, vilanterol (VI), to a once-daily ICS, fluticasone furoate (FF), on the risk of severe asthma exacerbations in patients with uncontrolled asthma. Methods This randomised double-blind comparative study of variable duration (≥24–78 weeks) was designed to finish after 330 events (each patient's first on-treatment severe asthma exacerbation). 2019 patients with asthma aged ≥12 years with ≥1 recorded exacerbation within 1 year were randomised and received FF/VI 100/25 μg or FF 100 μg, administered once daily in the evening. The primary endpoint was time to first severe exacerbation; secondary endpoints were rate of severe asthma exacerbations per patient per year and change in trough evening forced expiratory volume in 1 s (FEV1) from baseline. Results Compared with FF, FF/VI delayed the time to first severe exacerbation (HR 0.795, 95% CI 0.642 to 0.985) and reduced the annualised rate of severe exacerbations (rate reduction 25%, 95% CI 5% to 40%). Significantly greater improvements in trough FEV1 (p<0.001) were observed with FF/VI than with FF at weeks 12, 36, 52 and at endpoint. Both treatments were well tolerated with similar rates of treatment-related adverse events and on-treatment serious adverse events. Conclusions Once-daily FF/VI reduced the risk of severe asthma exacerbations and improved lung function compared with FF alone, with good tolerability and safety profile in adolescents and adults with asthma currently receiving ICS. ClinicalTrials.gov No NCT01086384

Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β(2) agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4-5 h for umeclidinium and median tlast of 1.5-2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone. Clinicaltrials.gov NCT00976144.

The INTREPID trial showed that once-daily single-inhaler triple therapy (SITT) using fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) offers clinical benefits versus non-ELLIPTA multiple-inhaler triple therapy (MITT) for the management of chronic obstructive pulmonary disease (COPD) in real-world clinical practice. This analysis evaluated the cost-effectiveness of SITT with FF/UMEC/VI versus non-ELLIPTA MITT for treating symptomatic COPD from a German healthcare perspective. Data from the INTREPID trial, including baseline characteristics, treatment effects (forced expiratory volume in 1 second and St. George's Respiratory Questionnaire score [derived from exploratory COPD assessment test score mapping]), and discontinuation rates, along with German healthcare resource and drug costs (2023 Euros), were used to populate the GALAXY COPD model. The analysis was conducted over a lifetime horizon, with outcomes including life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-utility ratios. The robustness of the analysis was assessed using scenario, one-way sensitivity, and probabilistic analyses. Improved lifetime outcomes were predicted for FF/UMEC/VI versus non-ELLIPTA MITT, providing additional LYs of 0.174 (95% range: 0.065, 0.322) and QALYs of 0.261 (0.186, 0.346) per patient, together with cost savings of €2,850 (€3,517, €2,220). Additionally, patients receiving FF/UMEC/VI were predicted to experience a reduction in exacerbations (-0.063), highlighting its dominance as the preferred treatment option. These findings remained consistent across one-way sensitivity, scenario, and probabilistic analyses, highlighting the robustness of FF/UMEC/VI as a cost-effective solution for COPD management in Germany. FF/UMEC/VI offers clinical benefits and cost savings compared with non-ELLIPTA MITT, suggesting that it may reduce the burden of COPD in Germany and warranting consideration as a preferred treatment option by physicians.

The frequency of COPD exacerbations during treatment with a triple inhaler — delivering a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled glucocorticoid — was compared with that with a LABA–LAMA or LABA–inhaled glucocorticoid.

We assessed the cost-effectiveness of single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI from a Canadian public healthcare perspective, incorporating data from the IMPACT trial in chronic obstructive pulmonary disease (COPD) (NCT02164513). Baseline inputs and treatment effects from IMPACT were populated into the validated GALAXY-COPD disease progression model. Canadian unit costs and drug costs (Canadian dollars [C$], 2017) were applied to healthcare resource utilization and treatments. Future costs and health outcomes were discounted at 1.5% annually. Analyses were probabilistic, and outputs included exacerbation rates, costs, and life years (LYs) and quality-adjusted life years (QALYs) gained. Compared with FF/VI and UMEC/VI over a lifetime horizon, the analyses predicted that treatment with FF/UMEC/VI resulted in fewer moderate and severe exacerbations, more LYs and more QALYs gained, with a small incremental cost. The base-case incremental cost-effectiveness ratio (ICER) per QALY gained was C$18,989 (95% confidence interval [CI]: C$14,665, C$25,753) versus FF/VI and C$13,776 (95% CI: C$9787, C$19,448) versus UMEC/VI. FF/UMEC/VI remained cost-effective versus both FF/VI and UMEC/VI in all sensitivity analyses, including in scenario analyses that considered different intervention and comparator discontinuation rates, and treatment effects for subsequent therapy. Treatment with FF/UMEC/VI was predicted to improve outcomes and be a cost-effective treatment option for patients with symptomatic COPD and a history of exacerbations compared with FF/VI or UMEC/VI, in Canada.

Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β -agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited. We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD. The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24. In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components. These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).

Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting β agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk. In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40–80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or the combination of fluticasone furoate (100 μg) and vilanterol (25 μg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov, number NCT01313676. Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74–1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77–1·08]; p=0·284; vilanterol, 0·96 [0·81–1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2·4] vs 46 mL per year [2·5] for placebo, difference 8 mL per year [95% CI 1–15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1–14]), but not vilanterol (difference −2 mL per year [95% CI −8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0·93 [95% CI 0·75–1·14]) with similar findings for fluticasone furoate (0·90 [0·72–1·11]) and vilanterol (0·99 [0·80–1·22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups. In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline. GlaxoSmithKline.