fluticasone-furoate and Pulmonary-Disease--Chronic-Obstructive

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Traditional efficacy double-blind randomised controlled trials (DBRCTs) measure the benefit a treatment produces under near-ideal test conditions in highly selected patient populations; however, the behaviour of patients and investigators in such trials is highly controlled, highly compliant and adherent, and non-representative of routine clinical practice. Pragmatic effectiveness trials measure the benefit a treatment produces in patients in everyday "real-world" practice. Ideally, effectiveness trials should recruit patients as similar as possible to those who will ultimately be prescribed the medicine, and create freedom within the study design to allow normal behaviours of patients and healthcare professionals (HCPs) to be expressed. The Salford Lung Study (SLS) was a world-first, prospective, phase III, pragmatic randomised controlled trial (RCT) programme in patients with chronic obstructive pulmonary disease and asthma to evaluate the effectiveness of a pre-licensed medication (fluticasone furoate/vilanterol) in real-world practice using electronic health records and through collaboratively engaging general practitioners and community pharmacists in clinical research. The real-world aspect of SLS was unique, requiring careful planning and attention to the goals of maximising the external validity of the trials while maintaining scientific rigour and securing suitable electronic processes for proper interpretation of safety data. Key learnings from SLS that may inform the design of future pragmatic effectiveness RCTs include: (1) ensuring the trial setting and operational infrastructure are aligned with routine clinical care; (2) recruiting a broad patient population with characteristics as close as possible to patients in routine clinical practice, to maximise the generalisability and applicability of trial results; (3) ensuring that patients and HCPs are suitably engaged in the trial, to maximise the chances of successful trial delivery; and (4) careful study design, incorporating outcomes of value to patients, HCPs, policymakers and payers, and using pre-planned analyses to address scientifically valid research hypotheses to ensure robustness of the trial data.

Topics: Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Therapy, Combination; Electronic Health Records; Health Behavior; Humans; Patient Selection; Product Surveillance, Postmarketing; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Reproducibility of Results

In this review, we focused on original manuscripts published in the 2017 that provided additional information on the clinical and therapeutic features of the chronic obstructive pulmonary disease (COPD). We have chosen eight of these studies, collected in four topics concerning the pharmacological treatment (tiotropium) of mild-moderate patients, the pharmacological (fluticasone furoate/vilanterol/umeclidinium) and non-pharmacological treatment (non-invasive mechanical ventilation) of severe patients, the etiology of acute exacerbation of COPD involving seasonal airway pathogens and the role of eosinophils with particular interest to the monoclonal antibody directed against interleukin-5 (mepolizumab). For each topic, we report a brief description of studies, take-home messages, and brief comments.

Topics: Androstadienes; Antibodies, Monoclonal, Humanized; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Common Cold; Disease Progression; Drug Combinations; Eosinophils; Glucocorticoids; Haemophilus Infections; Humans; Interleukin-5; Moraxellaceae Infections; Muscarinic Antagonists; Noninvasive Ventilation; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Seasons; Severity of Illness Index; Tiotropium Bromide

▼Trelegy Ellipta (GSK) is a dry powder inhaler containing fluticasone furoate (inhaled corticosteroid [ICS]), vilanterol trifenatate (long-acting beta

Topics: Administration, Inhalation; Androstadienes; Drug Combinations; Dry Powder Inhalers; Humans; Pulmonary Disease, Chronic Obstructive

Three classes of inhaler medication are used to manage chronic obstructive pulmonary disease (COPD): long-acting beta₂-agonists (LABA); long-acting muscarinic antagonists (LAMA); and inhaled corticosteroids (ICS). To encourage patient adherence, two classes of medication are often combined in a single medication device; it seems that once-daily dosing offers greatest convenience to patients and may markedly influence adherence.. To compare a once-daily combination of inhaled corticosteroid and long-acting beta₂-agonist inhalers (ICS/LABA) versus inhaled long-acting muscarinic antagonists alone (LAMA) for people with chronic obstructive pulmonary disease (COPD).. We performed an electronic search of the Specialised Register of the Cochrane Airways Group (14 May 2018), ClinicalTrials.gov (14 May 2018), and the World Health Organization International Clinical Trials Registry Platform (20 September 2017), then a search of other resources, including reference lists of included studies and manufacturers' trial registers (10 October 2017). Two pairs of review authors screened and scrutinised selected articles.. We included randomised controlled trials (RCTs) comparing once-daily administered ICS/LABA and LAMA in adults with COPD.. Two review authors independently extracted data and assessed risk of bias in each study. We analysed dichotomous data as random-effects odds ratios (ORs) and continuous data as mean differences (MDs), both with 95% confidence intervals (95% CIs), using Review Manager 5.. We included two studies with 880 participants. We identified one ongoing trial with planned recruitment of 80 participants. Included studies enrolled participants with both partially reversible and non-reversible COPD and baseline mean per cent predicted (%pred) forced expiratory volume in one second (FEV₁) of 43.4 to 49.6. Both studies lasted 12 weeks. Both studies used the same combination of inhaled ICS/LABA (fluticasone furoate and vilanterol 100/25 mcg once daily; FF/VI) versus LAMA (18 mcg tiotropium; TIO). They were published as full articles, and neither study was at low risk of bias in all domains.Compared to the TIO arm, results for pooled primary outcomes for the FF/VI arm were as follows: mortality: OR 0.20, 95% CI 0.02 to 1.73, 880 participants (deaths reported only in the TIO arm), very low-quality evidence; COPD exacerbation (requiring short-burst oral corticosteroids or antibiotics, or both): OR 0.72, 95% Cl 0.35 to 1.50, 880 participants, very low-quality evidence; pneumonia: reported in both studies only during treatment with FF/VI: OR 6.12, 95% Cl 0.73 to 51.24, 880 participants, very low-quality evidence; and total serious adverse events: OR 0.96, 95% Cl 0.50 to 1.83, 880 participants, very low-quality evidence. None of the pneumonias were fatal. Compared to the TIO arm, we found no statistically significant difference for pooled secondary outcomes, including St George's Respiratory Questionnaire (SGRQ) mean total score change; hospital admissions (all-cause); disease-specific adverse events; mean weekly rescue medication use (results available from only one of the studies); and mean weekly percentage of rescue-free days for FF/VI. We found no statistically significant differences between ICS/LABA and LAMA for improvement in symptoms measured by the COPD Assessment Test (CAT score) nor for FEV₁ (change from baseline trough in 24-hour weighted mean on treatment day 84). Many pooled estimates lacked precision. Data for other endpoints such as exacerbations leading to intubation and physical activity measures were not available in included trials.. Based on analysis of primary and secondary outcomes, we are uncertain whether once-daily ICS/LABA, combined in one inhaler, has a different efficacy or adverse effect profile compared to LAMA for treatment of people with COPD. However, the current review is based on only two trials with the main focus on primary outcomes other than those considered in this review. The short follow-up period and the very low quality of evidence limit our confidence in the result and increase uncertainty. Further trials of longer duration are needed. Current evidence is not strong enough to demonstrate important differences between inhalers in terms of effects, nor to establish that once-daily fluticasone/vilanterol 100/25 mcg and tiotropium 18 mcg are equivalent.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Drug Administration Schedule; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic

Current national and international guidelines for the management of patients with stable chronic obstructive pulmonary disease (COPD) recommend the use of inhaled long-acting bronchodilators, inhaled glucocorticoids and their combinations for maintenance treatment of moderate to severe stable COPD. Areas covered: The role of fluticasone furoate (FF) and vilanterol (VI) once daily combination therapy for the regular treatment of patients with stable COPD is discussed in this review. Expert commentary: The regular treatment of moderate to severe stable COPD with once daily FF/VI combination therapy is effective, as seen in in several large placebo-controlled clinical trials involving many thousands of patients. FF/VI improved lung function, decreased respiratory symptoms and decreased the number of COPD exacerbations, including COPD-related hospitalizations. FF/VI combination therapy has also been approved for this indication in most countries. The use of this combination therapy may significantly decrease the economic costs for some National Health Services.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Administration Schedule; Drug Combinations; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Androstadienes; Animals; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials as Topic; Drug Combinations; Glucocorticoids; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Recovery of Function; Research Design; Treatment Outcome

There is a considerable amount of evidence that supports the possibility of an increased risk of pneumonia associated with prolonged use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD). However, as yet, no statistically significant increase in pneumonia-related 30-day mortality in patients on ICS has been demonstrated. The lack of objective pneumonia definitions and radiological confirmations have been a major source of bias, because of the similarities in clinical presentation between pneumonia and acute exacerbations of COPD. One of the newer fluticasone furoate studies overcomes these limitations and also provides an assessment of a range of doses, suggesting that the therapeutic window is quite narrow and that conventional dosing has probably been too high, although the absolute risk may be different compared to other drugs. Newer studies were not able to rule out budesonide as responsible for pneumonia, as previous evidence suggested, and there is still need for evidence from head-to-head comparisons in order to better assess possible intra-class differences. Although the exact mechanisms by which ICS increase the risk of pneumonia are not fully understood, the immunosuppressive effects of ICS on the respiratory epithelium and the disruption of the lung microbiome are most likely to be implicated. Given that COPD represents such a complex and heterogeneous disease, attempts are being made to identify clinical phenotypes with clear therapeutic implications, in order to optimize the pharmacological treatment of COPD and avoid the indiscriminate use of ICS. If deemed necessary, gradual withdrawal of ICS appears to be well tolerated. Vaccination against pneumococcus and influenza should be emphasized in patients with COPD receiving ICS. Physicians should keep in mind that signs and symptoms of pneumonia in COPD patients may be initially indistinguishable from those of an exacerbation, and that patients with COPD appear to be at increased risk of developing pneumonia as a complication of ICS therapy.

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Glucocorticoids; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Fluticasone furoate/vilanterol (FF/VI) is a novel inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) fixed dose combination that, by simplifying the dosing schedule, allows, for the first time in a member of the ICS/LABA class, a shift from twice-daily to once-daily treatment. FF/VI is delivered via a novel, single-step activation, multi-dose dry powder inhaler for oral inhalation, Ellipta. Regrettably, there are no head-to-head trials that have shown superiority in the safety or efficacy of FF versus other ICSs, but evidence shows that VI has a quicker onset of effect versus salmeterol. However, the clinical utility of this effect in a maintenance medication is still questionable. Furthermore, benefits of FF/VI over twice-daily ICS/LABA comparator have not been shown yet and, in addition, its adverse event profile is generally consistent with the known class effects of an ICS/LABA fixed dose combination. In particular, there is an increase in the risk of pneumonia among patients treated with FF/VI relative to VI, mainly among those who benefit most from FF/VI. Nevertheless, the interesting pharmacological profiles of both FF and VI, the possibility that FF/VI can be administered once-daily, and the attractive characteristics of Ellipta are important features that could help FF/VI to be a successful combination in the treatment of chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Androstadienes; Animals; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Administration Schedule; Drug Combinations; Dry Powder Inhalers; Glucocorticoids; Humans; Lung; Powders; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) treatment approved in the United States, Canada and Europe for the long-term maintenance therapy of COPD. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes.. Data from 33 parallel-group randomised controlled trials (RCTs) of ICS/LABAs, of ≥8 weeks' duration in patients ≥12 years of age with COPD, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for three efficacy outcomes. Lung function, assessed by change from baseline in forced expiratory volume in one second (FEV1), was the outcome of primary interest (n = 28 studies). Secondary objectives were assessment of annual rate of moderate/severe exacerbations (n = 15) and patient-reported health status, measured by change from baseline in St George's Respiratory Questionnaire (SGRQ) Total score (n = 20). Overall, 25 different treatments were included in the MTC; we report findings, including probabilities of non-inferiority, for comparisons of once-daily FF/VI 100/25 mcg with twice-daily fluticasone propionate (FP)/salmeterol (SAL) 500/50 mcg and budesonide (BUD)/formoterol (FORM) 400/12 mcg.. For FEV1, FF/VI 100/25 mcg demonstrated >99% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg using a 50 mL margin. For annual rate of moderate/severe exacerbations, FF/VI 100/25 mcg demonstrated 73% and 77% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg, respectively, using a 10% rate ratio margin. For SGRQ Total score, the corresponding probabilities of non-inferiority were 99% and 98%, respectively, on a 2-unit margin. Significant covariate effects were identified: increased age was associated with deterioration in FEV1 and reduced exacerbation frequency; shorter study duration was associated with reduced exacerbation frequency.. FF/VI 100/25 mcg was comparable with corresponding doses of FP/SAL and BUD/FORM on lung function and health status outcomes. Non-inferiority on moderate/severe exacerbation rate was not demonstrated to the same degree of confidence, though observed rates were similar. Model limitations include a weak treatment network for the exacerbation analysis and variability across the included studies. Our data support previous RCT findings suggesting that the efficacy of FF/VI 100/25 mcg on lung function and health status in COPD is comparable with twice-daily ICS/LABAs.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Bayes Theorem; Benzyl Alcohols; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Chlorobenzenes; Disease Progression; Drug Administration Schedule; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Recovery of Function; Risk Factors; Time Factors; Treatment Outcome

To evaluate the efficacy and safety of the combination of fluticasone furoate/vilanterol (FF/VI) and compare it with other inhaled combination corticosteroid/long-acting β₂-receptor agonists for maintenance treatment of chronic obstructive pulmonary disease (COPD).. A PubMed and EMBASE search in June 2013 using the MeSH terms fluticasone and vilanterol identified trials using this combination for COPD. Additional information was gathered from references cited in the identified publications, the manufacturer, and package insert as well as the ClinicalTrials.gov registry.. Preference was given to randomized controlled clinical trials. Data from animal trials, clinical trials for asthma, and non-English sources were excluded.. Given once daily, FF/VI improves trough forced expiratory volume at 1 s by about 230 mL in a 28-day trial versus placebo. However, a more modest increase (100-130 mL) was seen in 2 longer 28-week trials. In the longest trial of 1 year, a slight but significant decrease in the yearly rate of moderate plus severe exacerbations, the time to first moderate or severe exacerbation, and the frequency of exacerbations requiring systemic corticosteroids was seen. There was no difference in the rate of exacerbations requiring hospitalization. The product appears to have the adverse effect profile typical of its class.. Of the inhaled corticosteroid/long-acting β₂ receptor agonist combinations, VI/FF is the first allowing once-daily dosing. Similar to the other combination products, it may slightly decrease the incidence of COPD exacerbations in the patient subset with Global Initiative for Chronic Obstructive Lung Disease risk category C or D. There are no direct safety or efficacy data comparing this with other available inhaled combination products. The once-daily dosing might improve adherence in select patients. The Ellipta delivery device may assist some who are unable to use other devices correctly.

Topics: Adrenergic beta-2 Receptor Agonists; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Forced Expiratory Volume; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive

Currently, there is no cure for chronic obstructive pulmonary disease (COPD). The limited efficacy of current therapies for COPD indicates a pressing need to develop new treatments to prevent the progression of the disease, which consumes a significant amount of health care resources and is an important cause of mortality worldwide. Current national and international guidelines for the management of stable COPD patients recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids, and their combination for maintenance treatment of moderate to severe stable COPD. Once-daily fluticasone furoate/vilanterol dry powder inhaler combination therapy has recently been approved by the US Food and Drug Administration and the European Medicines Agency as a new regular treatment for patients with stable COPD. Fluticasone furoate/vilanterol dry powder inhaler combination therapy has been shown to be effective in many controlled clinical trials involving thousands of patients in the regular treatment of stable COPD. This is the first once-daily combination of ultra-long-acting inhaled β2-agonists and inhaled glucocorticoids that is available for the treatment of stable COPD and has great potential to improve compliance to long-term regular inhaled therapy and hence to improve the natural history and prognosis of COPD patients.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Androstadienes; Animals; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Dry Powder Inhalers; Glucocorticoids; Humans; Powders; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Fluticasone furoate/vilanterol (Relvar(®), Breo(®), Revinty(®)) is a fixed combination of a corticosteroid and a long-acting β2-adrenergic agonist (LABA) for once-daily use via a dry powder inhaler (Ellipta(®)). Fluticasone furoate/vilanterol 100/25 µg is approved for the treatment of chronic obstructive pulmonary disease (COPD) in several countries. This article reviews the clinical use of the combination in COPD and summarises pharmacological properties. Fluticasone furoate has enhanced affinity for the glucocorticoid receptor compared with other clinically used inhaled corticosteroids (ICS) and longer lung retention than fluticasone propionate. Vilanterol is highly selective for β2-adrenoreceptors and provides a rapid and prolonged duration of action. In phase 3 trials in patients with moderate to very severe COPD, overall, once-daily fluticasone furoate/vilanterol 100/25 µg improved pulmonary function more than placebo and fluticasone furoate alone and improved exacerbation rates more than vilanterol alone. With regard to pulmonary function, once-daily fluticasone furoate/vilanterol 100/25 μg was more effective than twice-daily fluticasone propionate/salmeterol 250/50 µg and similarly effective as twice-daily fluticasone propionate/salmeterol 500/50 μg. In 12-month trials, fluticasone furoate/vilanterol was generally well tolerated, and in 12- and 24-week trials, the incidence of adverse events was similar overall to that associated with the individual components or fluticasone propionate/salmeterol. However, as with the long-term use of all ICS agents, 12-month data indicate an increase in the risk of pneumonia with fluticasone furoate/vilanterol. In conclusion, fluticasone furoate/vilanterol is an effective and generally well tolerated additional LABA/ICS agent for the treatment of COPD with the added convenience of once-daily administration, which may improve treatment adherence in some patients.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Dry Powder Inhalers; Glucocorticoids; Humans; Medication Adherence; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

In the Informing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler triple-therapy fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) reduced moderate/severe exacerbation rates vs FF/VI and UMEC/VI in patients with symptomatic COPD and a history of exacerbations, with a similar safety profile.. Are trial outcomes with single-inhaler triple-therapy FF/UMEC/VI vs FF/VI and UMEC/VI affected by age in patients with symptomatic COPD and a history of exacerbations?. IMPACT was a phase III, double-blind, 52-week trial. Patients ≥ 40 years of age with symptomatic COPD and ≥ 1 moderate/severe exacerbation in the previous year were randomly assigned 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. End points assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough FEV. FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status vs FF/VI and UMEC/VI irrespective of age for most end points, with a similar safety profile.. ClinicalTrials.gov; No.: NCT02164513; URL: www.clinicaltrials.govCTT116855.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Drug Monitoring; Female; Health Status Disparities; Humans; Male; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Respiratory Function Tests; Respiratory System Agents; Symptom Flare Up

Blood samples were obtained from the phase IIIA CAPTAIN study (ClinicalTrials.gov: NCT02924688), which evaluated the efficacy and safety of once-daily FF/UMEC/VI versus FF/VI in patients with uncontrolled asthma taking ICS/LABA. Samples were collected at trough (defined as ≥ 20 h after the last dose) from all subjects randomized to the six treatment groups (FF/UMEC/VI 100/31.25/25 μg, 100/62.5/25 μg, 200/31.25/25 μg, 200/62.5/25 μg; FF/VI 100/25 μg, 200/25 μg) at week 24 or the early withdrawal visit. In a subset of patients, PK samples were obtained predose at week 12, and at 5-30 min, 45-90 min, and 2-3 h postdose. For each analyte, a population PK model was developed using non-linear mixed-effects modeling. The maximum likelihood method was utilized to incorporate data below the quantifiable limit (BQL). Final models were used to derive the area under the plasma concentration-time curve and maximum observed concentration at steady-state for each analyte.. We obtained 4018, 2695, and 4032 samples from 1891, 1258, and 1891 patients, for FF, UMEC, and VI, respectively; 48%, 49%, and 50% of samples were reported as BQL for each analyte, respectively. The PK were adequately described by a two-compartment model with first-order absorption and elimination for FF, a two-compartment model with intravenous bolus input and first-order elimination for UMEC, and a three-compartment model with zero-order input and first-order elimination for VI. Statistically significant covariates were body weight on apparent inhaled clearance of FF, creatinine clearance on apparent clearance and body weight on apparent inhaled volume of distribution of the central compartment for UMEC, and race (East Asian, Japanese, and South East Asian heritage) on inhaled apparent volume of distribution of the central compartment for VI. However, the overall effects of covariates were marginal and thus do not warrant dose adjustment. Systemic exposures of FF or VI did not differ when administered as a single-inhaler triple (FF/UMEC/VI) or dual combination (FF/VI), and were similar to those reported for patients with chronic obstructive pulmonary disease.. Only marginal covariate effects were observed, and thus no dose adjustments are deemed necessary for FF, UMEC, or VI. There was no difference in FF or VI systemic exposure in patients with asthma when administered as either triple (FF/UMEC/VI) or dual therapy (FF/VI). Together with efficacy findings from the CAPTAIN study, our data support the use of single-inhaler FF/UMEC/VI triple therapy for patients with uncontrolled asthma currently receiving ICS/LABA.

Topics: Administration, Inhalation; Androstadienes; Asthma; Benzyl Alcohols; Bromides; Chlorobenzenes; Double-Blind Method; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Androstadienes; Angina, Unstable; Benzyl Alcohols; Cardiovascular Diseases; Cause of Death; Chlorobenzenes; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Ischemic Attack, Transient; Male; Middle Aged; Mortality; Myocardial Infarction; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Pulse Wave Analysis; Stroke; Treatment Outcome; Vascular Stiffness

Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0-4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0-4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board.. Sixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: - 2.2 beats per minute (bpm), 95% confidence interval [CI]: - 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0-4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred.. Six weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals.. Clinicaltrials.gov: NCT02573870 (submitted October 12, 2015).

Topics: Administration, Inhalation; Aged; Androstadienes; Carbamates; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinolones; Treatment Outcome

This analysis of the IMPACT study assessed the cardiovascular (CV) safety of single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI dual therapy.. IMPACT was a 52-week, randomized, double-blind, multicenter Phase III study comparing the efficacy and safety of FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg or UMEC/VI 62.5/25 mcg in patients ≥40 years of age with symptomatic chronic obstructive pulmonary disease (COPD) and ≥1 moderate/severe exacerbation in the previous year. The inclusion criteria for the study were intentionally designed to permit the enrollment of patients with significant concurrent CV disease/risk. CV safety assessments included proportion of patients with and exposure-adjusted rates of on-treatment CV adverse events of special interest (CVAESI) and major adverse cardiac events (MACE), as well as time-to-first (TTF) CVAESI, and TTF CVAESI resulting in hospitalization/prolonged hospitalization or death.. Baseline CV risk factors were similar across treatment groups. Overall, 68% of patients (n = 7012) had ≥1 CV risk factor and 40% (n = 4127) had ≥2. At baseline, 29% of patients reported a current/past cardiac disorder and 58% reported a current/past vascular disorder. The proportion of patients with on-treatment CVAESI was 11% for both FF/UMEC/VI and UMEC/VI, and 10% for FF/VI. There was no statistical difference for FF/UMEC/VI versus FF/VI or UMEC/VI in TTF CVAESI (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.85, 1.11; p = 0.711 and HR: 0.92, 95% CI: 0.78, 1.08; p = 0.317, respectively) nor TTF CVAESI leading to hospitalization/prolonged hospitalization or death (HR: 1.19, 95% CI: 0.93, 1.51; p = 0.167 and HR: 0.96, 95% CI: 0.72, 1.27; p = 0.760, respectively). On-treatment MACE occurred in ≤3% of patients across treatment groups, with similar prevalence and rates between treatments.. In a symptomatic COPD population with a history of exacerbations and a high rate of CV disease/risk, the proportion of patients with CVAESI and MACE was 10-11% and 1-3%, respectively, across treatment arms, and the risk of CVAESI was low and similar across treatment arms. There was no statistically significant increased CV risk associated with the use of FF/UMEC/VI versus FF/VI or UMEC/VI, and UMEC/VI versus FF/VI.. NCT02164513 (GSK study number CTT116855).

Topics: Aged; Androstadienes; Benzyl Alcohols; Cardiovascular Diseases; Chlorobenzenes; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines

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.. Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM. 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.. 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.

Topics: Administration, Inhalation; Aged; Androstadienes; Anticonvulsants; Benzyl Alcohols; Bromides; Chlorobenzenes; Drug Combinations; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Quinuclidines

The Study to Understand Mortality and Morbidity in COPD (SUMMIT) trial compared the efficacy of once-daily fluticasone furoate/vilanterol (FF/VI) with placebo, FF monotherapy, and VI monotherapy on mortality in patients with moderate chronic obstructive pulmonary disease (COPD) and a history/increased risk of cardiovascular (CV) disease. We conducted a post hoc economic analysis using data from SUMMIT to evaluate the economic benefits of treating these patients with COPD and CV risk.. Patients (aged 40-80 years, with ≥10 pack-years' smoking history and a risk of CV events) were randomized (1:1:1:1) to receive placebo, FF 100 mcg, VI 25 mcg, or FF/VI 100 mcg/25 mcg.. This was a post hoc economic analysis to assess the rates and associated costs of the composite end point (acute COPD exacerbations and revascularization/CV composite events) in the SUMMIT trial from a US healthcare payer perspective.. Overall, 16,485 patients were evaluated; of these, 5246 (31.8%) experienced an on-treatment composite end point event (28.5% experienced a COPD exacerbation, 4.2% experienced a CV event, and 2.0% underwent a revascularization procedure). The mean estimated 1-year on-treatment combined end point cost was highest for placebo and lowest for FF/VI ($4220 vs $3482, respectively). The reductions in cost versus placebo were significant for all active treatments (P <.0001). The likelihood of experiencing an on-treatment combined end point event was lower for patients treated with FF/VI versus placebo (hazard ratio, 0.81; P <.001).. One-year combined end point event costs were significantly lower for all active treatments versus placebo. Clinicians and payers may be able decrease costs by effectively managing patients' COPD in those with CV risk.

Topics: Adult; Aged; Aged, 80 and over; Androstadienes; Benzyl Alcohols; Cardiovascular Diseases; Chlorobenzenes; Costs and Cost Analysis; Drug Combinations; Female; Glucocorticoids; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; United States

The Informing the Pathway of COPD Treatment (IMPACT) study demonstrated that single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduces moderate/severe exacerbation rates and improves lung function and health status versus FF/VI or UMEC/VI dual therapy in patients with symptomatic COPD and a history of exacerbations. This analysis evaluated the efficacy and safety of FF/UMEC/VI in patients enrolled in Japan.. IMPACT was a 52-week, randomized, double-blind, multicenter study comparing FF/UMEC/VI 100/62.5/25 µg with FF/VI 100/25 µg or UMEC/VI 62.5/25 µg in patients ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the previous year. Endpoints included annual rate of on-treatment moderate/severe exacerbations (primary endpoint), time-to-first on-treatment moderate/severe exacerbation and change from baseline at Week 52 in trough FEV. The Japan subgroup accounted for only 4% (378/10,355) of the overall IMPACT intent-to-treat (ITT) population. In the Japan subgroup, FF/UMEC/VI reduced the annual rate of on-treatment moderate/severe exacerbations by 15% (95% CI: -20, 40) versus FF/VI (compared with 15% [10, 20] in the ITT) and 36% (95% CI: 6, 57) versus UMEC/VI (compared with 25% [19, 30] in the ITT). FF/UMEC/VI reduced moderate/severe exacerbation risk (time-to-first), improved lung function and health status at Week 52 versus both dual therapies. These results were in the same direction and of a generally similar magnitude to those seen in the overall ITT population. No new safety signals were identified in the Japan subgroup compared with the ITT population. Pneumonia incidence was higher with FF/UMEC/VI and FF/VI versus UMEC/VI.. These results highlight the favorable benefit-risk profile of FF/UMEC/VI single-inhaler triple therapy compared with FF/VI or UMEC/VI dual therapy in patients in Japan with symptomatic COPD and ≥1 exacerbation in the prior year.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Disease Progression; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Health Status; Humans; Japan; Lung; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Recovery of Function; Time Factors; Treatment Outcome

SLS COPD was the first open-label randomised controlled trial demonstrating a reduction in moderate/severe COPD exacerbations with once-daily inhaled fluticasone furoate/vilanterol (FF/VI) in everyday clinical practice. Here we report FF/VI effectiveness and safety in predefined patient subgroups.. Patients with COPD, exacerbation history, and receiving maintenance inhaler therapy, were randomised to initiate FF/VI 100/25 μg or continue usual care (UC) with 12 months' follow-up. Annual rates of moderate/severe exacerbations (primary outcome), selected secondary outcomes, and incidence of pneumonia serious adverse events of special interest (SAESI) were compared between randomisation groups across various patient subgroups/baseline treatment strata. SAESI rates by actual treatment were also assessed.. Lower exacerbation rates were observed for FF/VI versus UC across all subgroups/strata, including ICS + LABA therapy subset (8.0% [0.1, 15.4]), except in patients without baseline airflow limitation (-0.5% [-29.8, 22.1]). Larger reductions compared to the overall analysis were observed for patients on ICS-containing regimens (excluding LAMA) before the study (15.6% [3.4, 26.3]), and with baseline CAT score <10 (25.3% [-0.4, 44.4]). Pneumonia SAESI rates were similar for FF/VI versus UC across all subgroups/strata, except the LABA, LAMA or LABA + LAMA stratum (incidence ratio 2.8 [0.9, 8.5]). SAESI rates were not increased for FF/VI versus other ICS + LABA.. Initiating FF/VI versus continuing UC reduced exacerbation rates without increased pneumonia SAESI risk compared to other ICS-containing regimens and in various patient subgroups, consistent with primary study findings. FF/VI may be a therapeutic option for a broad population of COPD patients, including those with more severe disease.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Disease Progression; Female; Humans; Incidence; Lung; Male; Middle Aged; Muscarinic Antagonists; Pneumonia; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Safety

The Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) was a 12-month, Phase III, open-label, randomised study comparing the effectiveness and safety of initiating once-daily fluticasone furoate 100 µg/vilanterol 25 µg (FF/VI) with continuing usual care (UC). Follow-up interviews were conducted among a subset of 400 patients who completed SLS COPD to further understand patients' experiences with treatment outcomes and the impact of COPD, and potential risk factors associated with higher rates of exacerbations during SLS COPD. Another objective was to explore how such patient-centred outcomes differed by randomised treatment. Patients' perceived control over COPD and effects on quality of life (QoL) were similar between treatment groups at the time of the follow-up interview, but more patients in the FF/VI group compared with UC reported perceived improvements in COPD control and QoL during the study. Of patients who experienced ≥2 exacerbations during SLS COPD, a greater percentage were women, were unemployed or homemakers, or were on long-term sick leave. Having ≥2 exacerbations also appeared to be associated with smoking, seeing a hospital specialist, a feeling of having no/little control over COPD, perceived worsening of feelings of control and reduced overall QoL since the start of the study, being aware of impending exacerbation occurrence and a more severe last exacerbation. Initiation of FF/VI was associated with a greater perceived improvement in patients' control of their COPD and QoL throughout SLS COPD than continuation of UC. Suggestions that smoking status and feelings of control are potentially related to exacerbation require further investigation.

Topics: Aged; Androstadienes; Bendamustine Hydrochloride; Benzyl Alcohols; Chlorobenzenes; Female; Follow-Up Studies; Glucocorticoids; Humans; Interviews as Topic; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Symptom Flare Up

Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is of increasing interest because ACO patients have significantly worse outcomes, leading to greater social and economic burdens compared with asthma or COPD alone. Some guidelines for ACO recommend triple therapy with inhaled corticosteroids, long-acting β2 agonists, and long-acting muscarinic antagonists. However, this approach is based on extrapolating data from patients with asthma or COPD alone. Therapeutic studies for ACO have not previously been conducted.. A 12-week, randomized, open-label cross-over pilot study was conducted in 17 ACO patients to evaluate the effect of umeclidinium (UMEC) 62.5 µg once-daily added to fluticasone furoate/vilanterol (FF/VI) 200/25 µg once-daily. A 4-week run-in, a first and a second 4-week treatment period were included. Respiratory function, respiratory impedance, fractional exhaled nitric oxide, COPD assessment test, and asthma control test scores were evaluated 0, 4, and 8 weeks after randomization.. Adding UMEC to FF/VI provides greater improvement in lung function, indicating that triple therapy is a suitable regular treatment for ACO.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cross-Over Studies; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Japan; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Systemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic obstructive pulmonary disease (COPD) outcomes. However, they require validation in different cohorts.. Relate systemic levels of those proteins to forced expiratory volume in 1 s (FEV. In COPD, systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen were not associated with FEV. NCT01313676.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Biomarkers; Bronchodilator Agents; C-Reactive Protein; Chlorobenzenes; Drug Therapy, Combination; Feasibility Studies; Female; Fibrinogen; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Prognosis; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Receptor for Advanced Glycation End Products; Symptom Flare Up; Treatment Outcome; Uteroglobin

Previous studies have highlighted a relationship between reduction in rate of exacerbations with therapies containing inhaled corticosteroids (ICS) and baseline blood eosinophil count in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial showed that once-daily single-inhaler triple therapy significantly reduced exacerbations versus dual therapies. Blood eosinophil counts and smoking status could be important modifiers of treatment response to ICS. We aimed to model these relationships and their interactions, including outcomes other than exacerbations.. IMPACT was a phase 3, randomised, double-blind, parallel-group, 52-week global study comparing once-daily single-inhaler triple therapy (fluticasone furoate-umeclidinium-vilanterol) with dual inhaled therapy (fluticasone furoate-vilanterol or umeclidinium-vilanterol). Eligible patients had moderate-to-very-severe COPD and at least one moderate or severe exacerbation in the previous year. We used fractional polynomials to model continuous blood eosinophil counts. We used negative binomial regression for numbers of moderate and severe exacerbations, severe exacerbations, and pneumonia. We modelled differences at week 52 in trough FEV. The magnitude of benefit of regimens containing ICS (fluticasone furoate-umeclidinium-vilanterol n=4151 and fluticasone furoate-vilanterol n=4134) in reducing rates of moderate and severe exacerbations increased in proportion with blood eosinophil count, compared with a non-ICS dual long-acting bronchodilator (umeclidinium-vilanterol n=2070). The moderate and severe exacerbation rate ratio for triple therapy versus umeclidinium-vilanterol was 0·88 (95% CI 0·74 to 1·04) at blood eosinophil count less than 90 cells per μL and 0·56 (0·47 to 0·66) at counts of 310 cells per μL or more; the corresponding rate ratio for fluticasone furoate-vilanterol versus umeclidinium-vilanterol was 1·09 (0·91 to 1·29) and 0·56 (0·47 to 0·66), respectively. Similar results were observed for FEV. This analysis of the IMPACT trial shows that assessment of blood eosinophil count and smoking status has the potential to optimise ICS use in clinical practice in patients with COPD and a history of exacerbations.. GlaxoSmithKline.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Therapy, Combination; Eosinophils; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg has been shown to improve lung function and health status, and reduce exacerbations, versus budesonide/formoterol in patients with chronic obstructive pulmonary disease (COPD). We evaluated the non-inferiority of single-inhaler FF/UMEC/VI versus FF/VI + UMEC using two inhalers.. Eligible patients with COPD (aged ≥40 years; ≥1 moderate/severe exacerbation in the 12 months before screening) were randomized (1:1; stratified by the number of long-acting bronchodilators [0, 1 or 2] per day during run-in) to receive 24-week FF/UMEC/VI 100/62.5/25 μg and placebo or FF/VI 100/25 μg + UMEC 62.5 μg; all treatments/placebo were delivered using the ELLIPTA inhaler once-daily in the morning. Primary endpoint: change from baseline in trough forced expiratory volume in 1 s (FEV. Single-inhaler triple therapy (FF/UMEC/VI) is non-inferior to two inhalers (FF/VI + UMEC) on trough FEV. GSK study CTT200812; ClinicalTrials.gov NCT02729051 (submitted 31 March 2016).

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines

The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β. In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium-vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment.. The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001).. Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Dyspnea; Female; Glucocorticoids; Hospitalization; Humans; Intention to Treat Analysis; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines

A population pharmacokinetic analysis was conducted from a subset of samples obtained from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy trial to characterize the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol in patients with symptomatic COPD following treatment with fluticason furoate-umeclidinium-vilanterol combined in a single inhaler. This was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticason furoate-umeclidinium-vilanterol, 100 μg/62.5 μg/25 μg; Ellipta inhaler) with twice-daily dual therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). The analyses were conducted in a subset of 74 patients who received fluticason furoate-umeclidinium-vilanterol and provided serial or sparse samples. Monte Carlo simulations and a model-based estimation approach both indicated that systemic drug concentrations of fluticasone furoate, umeclidinium, and vilanterol after administration of fluticason furoate-umeclidinium-vilanterol triple combination therapy from a single inhaler were within the ranges observed following administration of these drugs as monotherapy (fluticasone furoate, umeclidinium, and vilanterol) or as dual-combination therapy (fluticasone furoate/vilanterol or umeclidinium/vilanterol).

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Female; Humans; Male; Middle Aged; Monte Carlo Method; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Random Allocation

Patients with chronic obstructive pulmonary disease (COPD) have increased risk of cardiovascular events.. This study evaluated the association between high-sensitivity cardiac troponin I concentration and cardiovascular events in patients with COPD and heightened cardiovascular risk.. In a double-blind randomized controlled trial, 16,485 patients with COPD and cardiovascular disease or risk factors were randomized to once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or their combination. Plasma high-sensitivity cardiac troponin I concentrations were measured in a subgroup of 1,599 patients. Outcomes were on-treatment cardiovascular events and COPD exacerbations over a median of 18 months, and cardiovascular death over a median of 27 months.. Baseline plasma cardiac troponin I concentrations were above the limit of detection (1.2 ng/l) in 1,542 (96%) patients. Concentrations were unaffected by inhaled therapies at 3 months (p > 0.05). Compared with the lowest quintile (cardiac troponin <2.3 ng/l), patients in the highest quintile (≥7.7 ng/l) were at greater risk of cardiovascular events (hazard ratio [HR] 3.7; 95% confidence interval [CI]: 1.3 to 10.1; p = 0.012) and cardiovascular death (HR: 20.1; 95% CI: 2.4 to 165.2; p = 0.005) after adjustment for risk factors. By contrast, there were no differences in exacerbations between quintiles (HR: 1.1; 95% CI: 0.8 to 1.5; p = 0.548).. In patients with COPD and heightened cardiovascular risk, plasma cardiac troponin I concentrations are a specific and major indicator of future cardiovascular events and cardiovascular death. Inhaled therapies did not affect cardiac troponin I concentrations consistent with their neutral effect on mortality and cardiovascular outcomes. (Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease [SUMMIT]; NCT01313676).

Topics: Aged; Androstadienes; Benzyl Alcohols; Biomarkers; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Double-Blind Method; Female; Glucocorticoids; Humans; Limit of Detection; Male; Middle Aged; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Risk; Troponin I

Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β. 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. 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).

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Budesonide; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines

Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) often coexist. We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk.. Participants were predominantly middle-aged (mean 65 (SD 8) years) men (75%) with overt CVD (66%). The composite CVD endpoint occurred in 688 patients (first event: sudden death (35%), acute coronary syndrome (37%) and stroke or TIA (23%), and was not reduced in any treatment group versus placebo: VI (HR 0.99, 95% CI 0.80 to 1.22), FF (HR 0.90, 95% CI 0.72 to 1.11) and their combination (HR 0.93, 95% CI 0.75 to 1.14). Outcomes were similar among all subgroups. Adverse events, including palpitations and arrhythmias, did not differ by treatment.. In patients with COPD with moderate airflow limitation and heightened CVD risk, treatment with inhaled VI, FF or their combination has an excellent safety profile and does not impact CVD outcomes.. NCT01313676.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Antagonists; Adult; Aged; Aged, 80 and over; Androstadienes; Benzyl Alcohols; Cardiovascular Diseases; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Factors; Treatment Outcome

The long-acting muscarinic antagonist, umeclidinium (UMEC), combined with the inhaled corticosteroid, fluticasone furoate (FF), improves lung function in symptomatic patients with asthma. We assessed FF/UMEC in patients with a primary diagnosis of asthma or chronic obstructive pulmonary disease (COPD), but physiological characteristics of both (fixed airflow obstruction and reversibility to salbutamol).. This double-blind, parallel-arm, 3-phase study randomised 338 patients (1:1:1:1:2:2) to FF 100 mcg alone or combined with UMEC (15.6, 62.5, 125, or 250 mcg) or vilanterol 25 mcg (Phase A, 4 weeks). Primary endpoint: change from baseline in clinic trough forced expiratory volume in 1 s (FEV

Topics: Adult; Aged; Albuterol; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Muscarinic Antagonists; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Inhaled corticosteroids have been shown to decrease exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Their effects in patients with milder airflow obstruction remain unclear.. This was an analysis of exacerbations in the SUMMIT (Study to Understand Mortality and Morbidity) study.. In a double-blind, randomized controlled trial, once-daily inhaled placebo, fluticasone furoate (FF; 100 μg), vilanterol (VI; 25 μg), or the combination of FF/VI was administered. The primary outcome was all-cause mortality. Exacerbations of COPD were an additional predefined endpoint. A total of 1,368 centers in 43 countries and 16,485 patients with moderate COPD and heightened cardiovascular risk were included in the study.. Patients with moderate chronic airflow obstruction experienced a reduction in exacerbations with FF/VI compared with placebo, irrespective of a history of exacerbations or baseline FEV

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Airway Obstruction; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Patients with chronic obstructive pulmonary disease develop increased cardiovascular morbidity with structural alterations.. To investigate through a double-blind, placebo-controlled, crossover study the effect of lung deflation on cardiovascular structure and function using cardiac magnetic resonance.. Forty-five hyperinflated patients with chronic obstructive pulmonary disease were randomized (1:1) to 7 (maximum 14) days inhaled corticosteroid/long-acting β2-agonist fluticasone furoate/vilanterol 100/25 μg or placebo (7-day minimum washout). Primary outcome was change from baseline in right ventricular end-diastolic volume index versus placebo.. There was a 5.8 ml/m(2) (95% confidence interval, 2.74-8.91; P < 0.001) increase in change from baseline right ventricular end-diastolic volume index and a 429 ml (P < 0.001) reduction in residual volume with fluticasone furoate/vilanterol versus placebo. Left ventricular end-diastolic and left atrial end-systolic volumes increased by 3.63 ml/m(2) (P = 0.002) and 2.33 ml/m(2) (P = 0.002). In post hoc analysis, right ventricular stroke volume increased by 4.87 ml/m(2) (P = 0.003); right ventricular ejection fraction was unchanged. Left ventricular adaptation was similar; left atrial ejection fraction improved by +3.17% (P < 0.001). Intrinsic myocardial function was unchanged. Pulmonary artery pulsatility increased in two of three locations (main +2.9%, P = 0.001; left +2.67%, P = 0.030). Fluticasone furoate/vilanterol safety profile was similar to placebo.. Pharmacologic treatment of chronic obstructive pulmonary disease has consistent beneficial and plausible effects on cardiac function and pulmonary vasculature that may contribute to favorable effects of inhaled therapies. Future studies should investigate the effect of prolonged lung deflation on intrinsic myocardial function. Clinical trial registered with www.clinicaltrials.gov (NCT 01691885).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cross-Over Studies; Drug Combinations; Female; Forced Expiratory Volume; Heart; Humans; Lung; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Pulmonary Disease, Chronic Obstructive

Fluticasone furoate/vilanterol (FF/VI) is a novel, once-daily, inhaled corticosteroid/long-acting β2-agonist combination approved for the treatment of COPD and asthma. We compared the safety and efficacy of FF/VI and tiotropium (TIO) in subjects with moderate-to-severe COPD with greater risk for comorbid cardiovascular disease (CVD).. This randomized, blinded, double-dummy, parallel-group study compared a once-daily morning dose of FF/VI 100/25 mcg delivered via ELLIPTA™ with TIO 18 mcg via HandiHaler(®) for 12 weeks in subjects with diagnosed COPD, forced expiratory volume in 1 second (FEV1) 30%-70% predicted, and CVD or CVD risk. The primary endpoint was change from baseline in 24-hour weighted mean FEV1 on Day 84. Other efficacy endpoints included time to onset of bronchodilation, trough FEV1, other spirometry measures, rescue medication use, symptoms, quality of life (St George's Respiratory Questionnaire-COPD [SGRQ-C]), and health status (COPD Assessment Tests [CAT]) measures. Safety endpoints included cardiovascular monitoring, cortisol excretion, COPD exacerbations, and adverse events, including prespecified drug effects.. Both FF/VI and TIO improved the 24-hour weighted mean FEV1 from baseline after 12 weeks with no significant difference between treatments. Other endpoints favored FF/VI for time to onset of bronchodilation, rescue medication use, dyspnea, SGRQ-C and CAT scores, or favored TIO for change from baseline in forced vital capacity and inspiratory capacity. Pneumonia occurred more frequently in the FF/VI group, and two TIO-treated subjects died following cardiovascular events. Other safety measures were similar between groups, and cardiovascular monitoring did not reveal increased CVD risk.. Both FF/VI and TIO were efficacious in improving lung function in subjects with COPD and comorbid CVD or CVD risk factors, with minor differences in efficacy and safety profiles.

Topics: Administration, Inhalation; Adult; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Drug Combinations; Drug Monitoring; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Symptom Assessment; Tiotropium Bromide; Treatment Outcome

To identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) versus LABA alone, in terms of exacerbation reduction, and to validate previously identified clusters of patients with chronic obstructive pulmonary disease (COPD) (based on diuretic use and reversibility).. Post hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year randomised, controlled trials of fluticasone furoate (FF)/vilanterol (VI) versus VI alone, with the primary end points of the annual rate of moderate-to-severe exacerbations.. Global.. 3255 patients with COPD (intent-to-treat populations) with a history of exacerbations in the past year.. FF/VI 50/25 µg, 100/25 µg or 200/25 µg, or VI 25 µg; all one time per day.. Mean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS (FF) to VI bronchodilator therapy.. Three clusters were identified, including two groups that benefit from FF/VI versus VI: patients with blood eosinophils >2.4% (RR=0.68, 95% CI 0.58 to 0.79), or blood eosinophils ≤2.4% and smoking history ≤46 pack-years, experienced a reduced rate of exacerbations with FF/VI versus VI (RR=0.78, 95% CI 0.63 to 0.96), whereas those with blood eosinophils ≤2.4% and smoking history >46 pack-years were identified as non-responders (RR=1.22, 95% CI 0.94 to 1.58). Clusters of patients previously identified in the fluticasone propionate/salmeterol (SAL) versus SAL trials of similar design were not validated; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility.. In patients with COPD with a history of exacerbations, those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations. In terms of eosinophils, this finding is consistent with findings from other studies; however, the validity of the 2.4% cut-off and the impact of smoking history require further investigation.. NCT01009463; NCT01017952; Post-results.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Disease Progression; Drug Therapy, Combination; Eosinophils; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Smoking; Treatment Outcome; United States

Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Phenotype; Practice Guidelines as Topic; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Evidence for the management of chronic obstructive pulmonary disease (COPD) comes from closely monitored efficacy trials involving groups of patients who were selected on the basis of restricted entry criteria. There is a need for randomized trials to be conducted in conditions that are closer to usual clinical practice.. In a controlled effectiveness trial conducted in 75 general practices, we randomly assigned 2799 patients with COPD to a once-daily inhaled combination of fluticasone furoate at a dose of 100 μg and vilanterol at a dose of 25 μg (the fluticasone furoate-vilanterol group) or to usual care (the usual-care group). The primary outcome was the rate of moderate or severe exacerbations among patients who had had an exacerbation within 1 year before the trial. Secondary outcomes were the rates of primary care contact (contact with a general practitioner, nurse, or other health care professional) and secondary care contact (inpatient admission, outpatient visit with a specialist, or visit to the emergency department), modification of the initial trial treatment for COPD, and the rate of exacerbations among patients who had had an exacerbation within 3 years before the trial, as assessed in a time-to-event analysis.. The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group. The numbers of other serious adverse events were similar in the two groups.. In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events. (Funded by GlaxoSmithKline; Salford Lung Study ClinicalTrials.gov number, NCT01551758 .).

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Drug Combinations; Female; Glucocorticoids; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive

Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date.. To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history.. Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 μg or VI 25 μg combined with 50, 100, or 200 μg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation.. Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 μg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index <25 kg/m(2), and severe airflow limitation.. Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigator-defined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management. Clinical trial registered with www.clinicaltrials.gov (NCT01009463 [HZC102871]; NCT01017952 [HZC102970]).

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Incidence; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; United States

Three strengths of fluticasone furoate/vilanterol (FF/VI) were previously evaluated for the treatment of chronic obstructive pulmonary disease (COPD) in a program of global Phase 3 studies that included only a small subgroup of Asian patients. This study further evaluated the efficacy and safety of the same three strengths of FF/VI exclusively in Asian patients.. A randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients with post-bronchodilator FEV1/FVC ≤0.70, FEV1 ≤70% predicted and modified Medical Research Council score ≥2 were randomized (1:1:1:1) to placebo, FF/VI 50/25 mcg, 100/25 mcg or 200/25 mcg once daily via the ELLIPTA dry powder inhaler. The primary efficacy endpoint was change from baseline in trough FEV1 at Week 24.. The intent-to-treat population comprised 643 patients. Statistically significant (p < 0.001) improvements in trough FEV1 were observed with all strengths of FF/VI versus placebo at Week 24 (0.14-0.19 L). Reduction of supplemental albuterol use was observed with all strengths of FF/VI versus placebo. The incidence of on-treatment adverse events (AEs) was 48% with FF/VI 200/25 mcg and 37-40% with other treatments. The incidence of on-treatment serious AEs was 4-9% with FF/VI treatments versus 9% with placebo; however, the study only covered a 6 month treatment period and was not powered to assess effects on exacerbations. No clinically significant treatment effects versus placebo were identified for electrocardiogram, vital signs, 24 hour urinary cortisol excretion and pneumonia.. All strengths of FF/VI improved lung function with an acceptable safety profile. There is no evidence to suggest that dose adjustment may be required in Asian patients using FF/VI 100/25 mcg for the treatment of COPD.. NCT01376245.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Asian People; Benzyl Alcohols; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Dry Powder Inhalers; Female; Glucocorticoids; Humans; Hydrocortisone; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are greater in patients with evidence of eosinophilic airway inflammation. We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency.. We did a post-hoc analysis of data from two replicate, randomised, double-blind trials of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg, 100 μg, or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year. We compared exacerbation rates according to two baseline eosinophil cell count strata (<2% and ≥2%), and according to four baseline percentage groupings. We also assessed lung function and incidence of pneumonia per strata in treatment groups.. We included 3177 patients in the analyses, with 2083 patients (66%) having an eosinophil count of 2% or higher at study entry. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0·91 vs 1·28 exacerbations per patient per year; p<0·0001) in patients with eosinophil counts of 2% or higher, and by 10% (0·79 vs 0·89; p=0·2827) in patients with eosinophil counts lower than 2%. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥2-<4%, 32% for those with counts of 4-<6%, and 42% for those with eosinophil counts of ≥6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category. Improvement in trough forced expiratory volume in 1 s (FEV1) and the increased risk of pneumonia with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count.. Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD. Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies.. GlaxoSmithKline (study ID 201595).

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Biomarkers; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Therapy, Combination; Eosinophils; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

The aim of these studies (NCT01957163; NCT02119286) was to evaluate the efficacy and safety of umeclidinium (UMEC 62.5 μg and 125 μg) added to fluticasone furoate/vilanterol (FF/VI, 100/25 μg) in chronic obstructive pulmonary disease (COPD).. These were 12-week, double-blind, placebo-controlled, parallel-group, multicenter studies. Eligible patients were randomized 1:1:1 to treatment with once-daily blinded UMEC 62.5 μg (delivering 55 μg), UMEC 125 μg (delivering 113 μg) or placebo (PBO) added to open-label FF/VI (delivering 92/22 μg; N = 1238 [intent-to-treat population]). The primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 85; the secondary endpoint was 0-6 h post-dose weighted mean (WM) FEV1 at Day 84. Health-related quality of life was reported using St George's respiratory questionnaire (SGRQ). Adverse events (AEs) were also assessed.. In both studies, trough FEV1 was significantly improved with UMEC + FF/VI (62.5 μg and 125 μg) versus PBO + FF/VI (range: 0.111-0.128 L, all p < 0.001 [Day 85]), as was 0-6 h post-dose WM FEV1 (range: 0.135-0.153 L, all p < 0.001 [Day 84]). SGRQ results were inconsistent, with statistically significant improvements with UMEC + FF/VI versus PBO + FF/VI in one study only and with UMEC 62.5 μg only (difference in SGRQ total score from baseline between treatments: -2.16, p < 0.05). Across all treatment groups, the overall incidences of AEs were similar (30-39%), as were cardiovascular AEs of special interest (<1-3%) and pneumonia AEs (0-1%).. Overall, the addition of UMEC to FF/VI therapy resulted in significant improvements in lung function compared with PBO + FF/VI in patients with COPD, with similar safety profiles, though SGRQ results were inconsistent.. The results from these two studies demonstrate that the addition of umeclidinium (62.5 μg and 125 μg) to FF/VI (100/25 μg) provides statistically significant and clinically meaningful improvements in lung function compared with placebo + FF/VI in patients with COPD. Statistically significant improvements in quality of life with UMEC + FF/VI versus placebo + FF/VI were reported in one study only. Safety profiles were consistent across all treatment groups in both studies. These studies support the use of triple therapy in COPD, providing physicians with an alternative treatment option.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Vital Capacity

New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy.. Patients with chronic obstructive pulmonary disease (COPD), ≥ 40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data.. The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in COPD.. Clinicaltrials.gov identifier NCT01551758.

Topics: Administration, Inhalation; Adult; Aerosols; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Protocols; Disease Progression; Drug Administration Schedule; Drug Combinations; Dry Powder Inhalers; Electronic Health Records; England; Female; Glucocorticoids; Humans; Lung; Male; Pulmonary Disease, Chronic Obstructive; Research Design; Time Factors; Treatment Outcome

Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is important because patients with ACOS have significantly worse outcomes compared with those with asthma or chronic obstructive pulmonary disease (COPD) alone. Inhaled corticosteroids (ICS), together with a long-acting β2 agonist (LABA), are recommended, but no therapeutic studies for ACOS have been conducted. Recently, fluticasone furoate/vilanterole (FF/VI) has been approved as the first once-daily ICS/LABA combination therapy for asthma and COPD.. A 12-week, randomized, open-label cross-over study was conducted in 16 patients with ACOS to compare the effectiveness of once-daily FF/VI 200/25 μg vs. twice-daily fluticasone propionate/salmeterol (FP/SAL) 500/50 μg. The study period included a 4-week run-in, the first 4-week treatment, and the second 4-week treatment. Respiratory functions, including forced expiratory volume in 1 s (FEV1) and respiratory impedance using the forced oscillation technique (FOT), were measured, as was fractional exhaled nitric oxide (FeNO). A COPD assessment test (CAT) scores and asthma control test (ACT) scores were recorded 0, 4, and 8 weeks after randomization.. The mean values for the FEV1 were 1.33 (±0.29) L in the run-in period, 1.38 (±0.39) L after the FP/SAL treatment period, and 1.47 (±0.38) L after the FF/VI treatment period. The FEV1 value after the FF/VI treatment was significantly greater than the value after the run-in period (p < 0.01). FOT parameters, FeNO levels, CAT scores, ACT scores, and other blood tests were not significantly different during the run-in period, the FP/SAL treatment period, and the FF/VI treatment period.. FF/VI, the first once-daily ICS/LABA, can provide substantial improvement in lung functions, indicating that FF/VI should be considered for the regular treatment of ACOS.

Topics: Aged; Aged, 80 and over; Androstadienes; Anti-Asthmatic Agents; Asthma; Benzyl Alcohols; Chlorobenzenes; Cross-Over Studies; Double-Blind Method; Drug Combinations; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Male; Middle Aged; Nitric Oxide; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Fluticasone furoate/vilanterol trifenatate (FF/VI) is a once-daily inhaled corticosteroid/long-acting β₂-agonist combination in development for chronic obstructive pulmonary disease (COPD) treatment. We compared the efficacy and safety of FF/VI versus fluticasone propionate/salmeterol (FP/SAL) twice daily over 12 weeks. Moderate to very severe COPD patients received FF/VI 100/25 μg once daily in the morning (n=266) or FP/SAL 500/50 μg twice daily (n=262). The primary end-point was a change from baseline in 0-24 h weighted mean forced expiratory volume in 1 s (wmFEV₁) at 12 weeks. Additional end-points included time to 100 mL improvement from baseline on day 1 and a change from baseline in St George's Respiratory Questionnaire (SGRQ). Safety was also assessed. wmFEV₁ (mean 130 mL) was greater and time to 100 mL improvement shorter (median 16 min) with FF/VI than FP/SAL (weighted mean 108 mL, median 28 min). Health status (SGRQ total score) improved in both groups (FF/VI -4.3 units, FP/SAL -3.0 units). Differences between treatments were not statistically significant. Six patients in the FF/VI (2%) and three in the FP/SAL (1%) arm experienced serious adverse events, none of which were considered to be drug related. Improvements in lung function and health status were not significantly different between FF/VI 100/25 μg once daily and FP/SAL 500/50 μg twice daily; there was no apparent difference between the safety profiles of either therapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Smoking; Surveys and Questionnaires; Treatment Outcome

The inhaled corticosteroid fluticasone furoate (FF) and the long-acting β₂ agonist vilanterol (VI) are in development as a combined once-daily therapy for asthma and chronic obstructive pulmonary disease. Our study objectives were to compare the efficacy and safety of once-daily FF/VI with FF alone and twice-daily fluticasone propionate (FP) in patients aged ≥12 years with moderate-to-severe persistent asthma. Patients (n=586) received FF/VI 200/25 μg or FF 200 μg once-daily (evening dosing), or FP 500 μg twice-daily for 24 weeks. Co-primary end-points were change from baseline in trough forced expiratory volume in 1 s (FEV₁) weighted mean (wm) 0-24 h serial FEV1. Secondary end-points included change from baseline in percentage of rescue-free 24-h periods, percentage of symptom-free 24-h periods and total Asthma Quality of Life Questionnaire (AQLQ). Safety assessments included adverse events, 24-h urinary cortisol excretion, vital signs and ECG. FF/VI significantly improved trough FEV1 and wmFEV₁ versus FF and FP. Significantly more rescue-free and symptom-free 24-h periods were reported with FF/VI versus FF. Treatment differences for AQLQ were not significant. Incidence of adverse events was similar across groups. No clinically significant differences were seen for 24-h urinary cortisol excretion, vital signs or ECG. FF/VI resulted in statistically greater improvements in lung function and symptomatic end-points versus FF, and was well tolerated in this asthma population.

Topics: Adult; Androstadienes; Anti-Asthmatic Agents; Asthma; Benzyl Alcohols; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Electrocardiography; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Hydrocortisone; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Pneumonia poses a significant risk in patients with moderate to severe chronic obstructive pulmonary disease but data are limited on the disease phenotypes most susceptible to pneumonia.. Cluster analysis using a data-driven recursive partitioning algorithm was employed using baseline data from two pooled one-year randomized exacerbation trials (n=3,255) of fluticasone furoate/vilanterol or vilanterol alone to identify distinct patient groups at greatest risk of pneumonia or serious (hospitalization or death) pneumonia.. Five clusters were identified. Patients at greater risk of first pneumonia had more severe obstruction (forced expiratory volume in one second/forced vital capacity <46%) and either a body mass index <19 kg/m(2) (hazard ratio 7.8, 95% confidence interval 4.7-13.0; n=144) or a pneumonia history and greater comorbidities (hazard ratio 4.8, 95% confidence interval 3.0-7.7; n=374) relative to the cluster with the lowest pneumonia risk (reference; n=1310). Multiple comorbidities and use of psychoanaleptics also contributed to an increased risk of pneumonia in more obstructed patients. Independent of cluster, use of inhaled corticosteroids was associated with pneumonia (hazard ratio 1.89, 95% confidence interval 1.25-2.84) and serious pneumonia (hazard ratio 2.92, 95% confidence interval 1.40-6.01).. Cluster analysis can identify patient populations at risk for serious safety outcomes and inform risk management strategies to optimize patient management. The greatest risk for pneumonia was in subjects with multiple pneumonia risk factors.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cluster Analysis; Comorbidity; Disease Progression; Female; Hospitalization; Humans; Lung; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors

Fluticasone furoate/vilanterol (FF/VI) is an inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA), recently approved as once-daily maintenance therapy for COPD. We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol (FP/SAL).. Three 12 week studies comparing FF/VI and FP/SAL were conducted. Patients aged ≥40 years with moderate-to-very severe COPD were randomized to receive double-blind, double-dummy FF/VI 100/25 mcg once-daily, or FP/SAL 250/50 mcg twice-daily for 12 weeks following a 2 week placebo run-in period. The primary endpoint of each study was change from baseline trough in 0-24 h weighted mean FEV(1) (wmFEV(1)) on Day 84. Safety was also assessed.. In Study 1 (HZC113109) (intent-to-treat n: FF/VI = 260; FP/SAL = 259), the increase from baseline in 0-24 h wmFEV(1) was significantly greater with FF/VI than FP/SAL (Δ80 mL, P < 0.001). In Study 2 (HZC112352) (intent-to-treat n: FF/VI = 259; FP/SAL = 252) and Study 3 (RLV116974) (intent-to-treat n: FF/VI = 412; FP/SAL = 416), the increase from baseline in 0-24 h wmFEV(1) was not significantly greater with FF/VI than FP/SAL (Δ29 mL, P = 0.267; Δ25 mL, P = 0.137). The treatment difference was statistically but not clinically significant in a pooled analysis (Δ41 mL, P < 0.001). Pooled adverse events (FF/VI 27%; FP/SAL 28%) and serious adverse events (FF/VI 2%; FP/SAL 3%) were similar between treatments.. Our data suggest that once-daily FF/VI 100/25 mcg provides FEV(1) improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg, although interpretation is limited by differences in individual study outcomes. The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar.. clinicaltrials.gov: NCT01323634; NCT01323621; NCT01706328. GlaxoSmithKline study codes: HZC113109; HZC112352; RLV116974.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Dry Powder Inhalers; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Vital Capacity

Increased arterial stiffness as measured by aortic pulse wave velocity (aPWV) predicts cardiovascular events and mortality and is elevated in patients with COPD. Prior investigation suggests that a long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) lowers aPWV in patients with baseline aPWV ≥ 11 m/s. This study compared the effect of the ICS/LABA fluticasone furoate/vilanterol (FF/VI), 100/25 μg, delivered via the ELLIPTA dry powder inhaler, with tiotropium bromide (TIO), 18 μg, on aPWV.. This multicenter, randomized, blinded, double-dummy, parallel-group, 12-week study compared FF/VI and TIO, both administered once daily. The primary end point was aPWV change from baseline at 12 weeks. Safety end points included adverse events (AEs), vital signs, and clinical laboratory tests.. Two hundred fifty-seven patients with COPD and aPWV ≥ 11 m/s were randomized; 87% had prior cardiovascular events and/or risk. The mean difference in aPWV between FF/VI and TIO at week 12 was not significant (P = .484). Because the study did not contain a placebo arm, a post hoc analysis was performed to show that both treatments lowered aPWV by an approximate difference of 1 m/s compared with baseline. The proportion of patients reporting AEs was similar with FF/VI (24%) and TIO (18%). There were no changes in clinical concern for vital signs or clinical laboratory tests.. No differences on aPWV were observed between FF/VI and TIO. However, further studies with a placebo arm are required to establish definitively whether long-acting bronchodilators lower aPWV. Both treatments demonstrated an acceptable tolerability profile.. ClinicalTrials.gov; No.: NCT01395888; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulse Wave Analysis; Respiratory Function Tests; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Vascular Stiffness

Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2) agonist is more protective than a once-daily longacting β(2) agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone.. We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV(1)) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV(1) of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952).. 1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 [95% CI 0·7-1·0]). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group.. Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.. GlaxoSmithKline.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Monitoring; Female; Glucocorticoids; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Respiratory System; Risk Assessment; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) often coexists with other chronic diseases and comorbidities that can markedly influence patients' health status and prognosis. This is particularly true for cardiovascular disease (CVD). However, there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases. The "Study to Understand Mortality and Morbidity in COPD" (SUMMIT) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD. SUMMIT is a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial of 16 000 patients with moderate COPD randomly assigned to once daily treatment with fluticasone furoate/vilanterol (100/25 μg), fluticasone furoate (100 μg), vilanterol (25 μg) or matched placebo; mortality is the primary end-point. The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo. Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point. This article describes the design of the SUMMIT study.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Androstadienes; Benzyl Alcohols; Cardiovascular Diseases; Chlorobenzenes; Double-Blind Method; Female; Forced Expiratory Volume; Health Status; Humans; International Cooperation; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Time Factors; Treatment Outcome

Once-daily combination treatment is an attractive maintenance therapy for COPD. However, the dose of inhaled corticosteroid to use in a once-daily combination is unknown. We compared two strengths of fluticasone furoate (FF) plus vilanterol (VI), the same strengths of the individual components, and placebo.. Multicentre, randomised, 24-week, double-blind, placebo-controlled, parallel-group study in stable, moderate-to-severe COPD subjects (N = 1224). Subjects were randomised to FF/VI (200/25 μg; 100/25 μg), FF (200 μg; 100 μg), VI 25 μg, or placebo, once daily in the morning. Co-primary efficacy endpoints; 0-4 h weighted mean (wm) FEV(1) on day 168, and change from baseline in trough (23-24 h post-dose) FEV(1) on day 169. The primary safety objective was adverse events (AEs).. There was a statistically significant (p < 0.001) increase in wm FEV(1) (209 ml) and trough FEV(1) (131 ml) for FF/VI 200/25 μg vs. placebo; similar changes were seen for FF/VI 100/25 μg vs. placebo. Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1) (32 ml) was not statistically significant (p = 0.224), the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1) (168 ml) was significantly different (p < 0.001). VI 25 μg significantly improved wm and trough FEV(1) vs. placebo (185 ml and 100 ml, [corrected] respectively). No increase was seen in on-treatment AEs or serious AEs (SAEs), with active therapy vs. placebo.. FF/VI provides rapid and significant sustained improvement in FEV(1) in subjects with moderate-to-severe COPD, which was not influenced by the dose of FF. These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study. GSK study number: HZC112207. ClinicalTrials.gov: NCT01054885.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Fluticasone furoate (FF)/vilanterol (VI) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD. We aimed to assess the efficacy and safety of two strengths of FF/VI (100/25 μg; 50/25 μg) vs. individual components (FF 100 μg, VI 25 μg) and placebo over 24 weeks.. Multicentre, randomised, placebo-controlled, double-blind, parallel-group study of patients (N = 1030) with moderate-to-severe COPD. All medication was administered once daily in the morning. Co-primary efficacy endpoints were: (1) weighted mean (wm) FEV1 (0-4 h post-dose on day 168) to assess acute lung function effects; and (2) trough FEV1 (23-24 h post-dose on day 169) to assess long-lasting effects. Symptom-related outcomes were analysed and adverse events (AEs) assessed.. Main findings were: (1) the combination of FF/VI at a strength of 100/25 μg significantly (p < 0.001) improved wm FEV1 (173 ml) and trough FEV1 (115 ml) vs. placebo. Similar effects were observed with FF/VI 50/25 μg; (2) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 (48 ml, p = 0.082), while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 (120 ml, p < 0.001); (3) VI 25 μg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 (103 ml, p < 0.001) and trough FEV1 (67 ml, p = 0.017); and (4) no safety signal was observed.. In subjects with moderate-to-severe COPD, FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks. Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg. All treatments were well tolerated. GSK study number: HZC112206. ClinicalTrials.gov: NCT01053988.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Available inhaled corticosteroid/long-acting β(2)-agonist combinations for chronic obstructive pulmonary disease (COPD) require twice-daily administration. The combination of fluticasone furoate (FF) and vilanterol (VI) FF/VI is being developed in a novel dry powder inhaler for the treatment of COPD and asthma with the potential for once-daily dosing. Results from Phase II studies have shown clinically and statistically significant improvements over placebo in trough (24-hour postdose) forced expiratory volume in 1 second (FEV(1)) after once-daily dosing with FF or VI (VI concurrently with an inhaled corticosteroid) in asthma and VI in COPD.. This Phase III, multicenter, randomized, double-blind, placebo-controlled study was designed based on guidance from drug regulators with the goal of evaluating the 24-hour spirometric effect of once-daily FF/VI in patients with COPD.. Patients (aged ≥40 years) who completed a 2-week placebo run-in period were randomized to 1 of 18 three-course sequences of placebo and 2 of 3 dose combinations of FF/VI (50/25 μg, 100/25 μg, and 200/25 μg), dosed once daily in the morning. Each 28-day treatment period was separated by a 2-week, single-blind, placebo washout period. The primary end point was time-adjusted (weighted mean) 0 to 24-hour FEV(1) (AUC) at the end of each 28-day treatment period (period days 28-29). Safety profile assessments included incidence of adverse events (AEs) (defined according to the Medical Dictionary for Regulatory Activities), 12-lead ECG outputs, vital signs (pulse rate, diastolic and systolic blood pressure) and clinical laboratory assessments (including fasting serum glucose and potassium) and 24-hour serum cortisol. The pharmacokinetics of FF and VI were assessed at the end of each 28-day treatment period with FF/VI.. Eighty-seven patients were screened; 54 completed run-in and were randomized to double-blind treatment. The mean patient age was 57.9 years, and 46% were male. The majority of patients were current smokers (83%) and were receiving short-acting β(2)-agonists within the 3 months before screening (63%). All 3 strengths of once-daily FF/VI demonstrated significantly higher 0 to 24-hour (period days 28-29) change from period baseline weighted mean FEV(1) than placebo: adjusted mean improvements from placebo in FEV(1) for FF/VI were 220 to 236 mL (all, P < 0.001). Improvements versus placebo in change from period baseline serial FEV(1) measures were observed at each time-point and with each strength of FF/VI over the 0 to 25-hour period (period days 28-29), indicating sustained bronchodilation. The overall incidence of on-treatment AEs was low (10%-12% with FF/VI; 4% with placebo); 2 serious AEs were reported during washout periods (1 AE after FF/VI 50/25 μg and 1 AE after placebo) but neither was considered treatment related. No serious AEs were reported during the treatment periods or during the follow-up period. No clinically or statistically significant differences from placebo were reported for serum glucose or potassium. No significant effects on vital signs, ECG, or 24-hour serial serum cortisol were reported. The extent of systemic exposure to FF and VI at steady state was low for all strengths of FF/VI.. FF/VI inhaled once daily in the morning for 28 days produced significant improvements in pulmonary function with a prolonged (>24 hours') duration of action in this population of patients with COPD. The combination was well tolerated. ClinicalTrials.gov identifier: NCT01072149.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aerosols; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Powders; Pulmonary Disease, Chronic Obstructive; Spirometry; Time Factors; Treatment Outcome; United States; Vital Capacity

To examine the impact of initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in a single device on chronic obstructive pulmonary disease (COPD) exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related healthcare resource utilization (HCRU) and costs in patients with COPD.. Retrospective database analysis of patients with COPD aged ≥40 years who initiated FF/UMEC/VI between September 1, 2017, and December 31, 2018 (index date: first pharmacy claim for FF/UMEC/VI), following evidence of multiple-inhaler triple therapy (MITT) (≥30 consecutive days) in the year prior to index. COPD exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related HCRU and costs were compared between the baseline period (12 months prior to and including index) and follow-up period (12 months following index).. Data from 912 patients (mean [SD] age: 71.2 [8.1], 51.2% female) were included in the analyses. Among the overall cohort, mean count of total COPD exacerbations (moderate or severe) per patient was statistically significantly lower in the follow-up period compared to baseline (1.2 vs 1.4, p=0.001). The proportion of patients with ≥1 COPD exacerbation (moderate or severe) was also statistically significantly lower in the follow-up period compared to baseline (56.4% vs 62.4%, p=0.001). All-cause and COPD-related HCRU were similar during follow-up compared to baseline, although the proportion of patients with COPD-related ambulatory visits was lower during follow-up (p<0.001). COPD-related office visit costs, emergency room visit costs, and pharmacy costs were statistically significantly lower during follow-up compared to baseline (p<0.001; p=0.019; p<0.001, respectively).. In a real-world setting, patients on MITT who subsequently initiated FF/UMEC/VI in a single device had significant reductions in the rate of COPD exacerbations (moderate or severe). Switching to FF/UMEC/VI also resulted in improvements in some HCRU and cost outcomes. These data support the use of FF/UMEC/VI among patients at high risk of exacerbation to reduce future risk and improve outcomes.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Female; Fluticasone; Humans; Male; Patient Acceptance of Health Care; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies

ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history.. COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated.. Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup.. These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Patient Acceptance of Health Care; Pneumonia; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide

Fluticasone furoate/vilanterol (FF/VI; RELVAR ELLIPTA) is approved in Korea for patients with asthma or chronic obstructive pulmonary disease (COPD). This study evaluated the effectiveness and safety of FF/VI in Korean patients with asthma and/or COPD over a 6-year period.. This was an open-label, multicentre, observational, post-marketing surveillance study in patients newly treated with FF/VI (100 or 200 μg/25 μg once daily). Safety endpoints were the incidence of adverse events (AEs), including unexpected AEs/adverse drug reactions (ADRs) and serious AEs/ADRs. Effectiveness was assessed after 24 weeks by Global Physician Assessment (logistic regression) and forced expiratory volume in 1 s (FEV. Of the 3426 patients enrolled across 45 hospitals between July 2014 and June 2020, 3216 were included in the safety analysis (50.5% female; mean age ± standard deviation [SD]: 58.6 ± 16.3 years). Overall incidence of AEs was 30.9% (n = 992); 4.1% (n = 132) were ADRs. Serious AEs were reported in 4.1% (n = 132) of patients; 0.1% (n = 4) were ADRs. Of 1543 patients analysed for symptomatic improvement, 89.2% (n = 1377) improved, 9.4% (n = 145) were unchanged, and 1.4% (n = 21) worsened. Mean FEV. In this real-world study, FF/VI administered to Korean patients was well tolerated and effective for the treatment of asthma and COPD. These results were consistent with other studies in Asian and global populations.

Topics: Administration, Inhalation; Asthma; Drug Combinations; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Republic of Korea; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by long-term breathing problems and airflow limitations. International guidelines recommend using bronchodilators like long-acting beta- and muscarinic antagonists, and inhalational corticosteroids.. The cost-effectiveness of single-inhaler triple therapy containing fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) was compared to the treatments Fluticasone Furoate/Vilanterol (FF/VI), Umeclidinio/Vilanterol (UMEC/VI) and Fluticasone Propionate 250 mcg/Salmeterol 25mcg + Tiotropio 18 mcg (FP/SAL/TIO) for patients with COPD from the Chilean public health system perspective.. A cost-effectiveness analysis was performed, including a deterministic and probabilistic sensitivity analysis over a 25-year time horizon. Two scenarios were assessed to study the effect of a 3%-discount for costs and outcomes on FF/UMEC/VI.. The incremental cost-effectiveness (ICER) of FF/UMEC/VI versus FF/VI was $10,076/QALY, being a cost-effective alternative to a threshold of one Gross Domestic Product per capita (GDPpc), while versus FP/SAL/TIO the ICER increased to $50,288/QALY, showing to be a non-cost effective alternative to 1 GDPpc, but at a threshold of 3 GDPpc.. FF/UMEC/VI appears to be a cost-effective intervention for treating COPD compared to FF/VI. However, FF/UMEC/VI compared to FP/SAL/TIO showed an ICER above the threshold of 1 GDPpc, but, in comparison with lower price, the ICER was below 3 GDPpc.

Topics: Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chile; Chlorobenzenes; Cost-Benefit Analysis; Double-Blind Method; Drug Combinations; Fluticasone; Forced Expiratory Volume; Humans; Public Health; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Single inhaler triple therapy (SITT) with an inhaled corticosteroid, a long-acting β. The preclinical and clinical development in COPD of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) SITT and its use in the real world.. Findings from phase III/IV trials and the use of FF/UMEC/VI in the real-world setting support the view that it may be a useful, safe, and cost-effective option for the maintenance treatment of COPD, especially when dealing with patients who are not adequately controlled with dual ICS/LABA or LAMA/LABA therapy. Only direct head-to-head comparisons will be able to establish whether FF/UMEC/VI may be preferable to the other SITTs approved for COPD due to its pharmacokinetic and pharmacodynamic characteristics and especially the fact that it is the only one that can be taken once-daily. In addition, there is a need for further studies, especially in the real world, to optimize the positioning of FF/UMEC/VI in the treatment of COPD, also considering the availability of FF/VI and UMEC/VI and the need for better differentiation between the three treatments.

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Androstadienes; Benzyl Alcohols; Chlorobenzenes; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Androstadienes; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Concerns have been raised about the practical use and clinical benefits of medications and inhalers in older patients with chronic obstructive pulmonary disease (COPD). Here, we report analyses according to age from five clinical trials evaluating medications administered using the ELLIPTA dry-powder inhaler (DPI).. Efficacy and safety according to age groups (<65 and ≥65 years) were assessed using data from five clinical trials in patients ≥40 years of age with symptomatic COPD. There was a mix of pre-specified and post hoc analyses of two 24-week trials with fluticasone furoate (FF)/vilanterol (VI) 100/25 µg; one 24-week trial with umeclidinium (UMEC) 62.5 µg; and two 12-week trials with UMEC 62.5 µg + FF/VI 100/25 µg. The primary endpoint was trough forced expiratory volume in 1 second (FEV. These data provide evidence to support the use of FF/VI, UMEC, or UMEC + FF/VI, all delivered via the ELLIPTA DPI, to treat older (≥65 years) and younger (<65 years) patients with COPD.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Androstadienes; Benzyl Alcohols; Chlorobenzenes; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Androstadienes; Asthma; Benzyl Alcohols; Chlorobenzenes; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Androstadienes; Asthma; Benzyl Alcohols; Chlorobenzenes; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality.. A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%).. A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

Topics: Androstadienes; Angina, Unstable; Benzyl Alcohols; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Clinical Trials Data Monitoring Committees; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Humans; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Factors; Stroke

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.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Canada; Chlorobenzenes; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Disease Progression; Drug Combinations; Drug Costs; Female; Humans; Lung; Male; Models, Economic; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quality-Adjusted Life Years; Quinuclidines; Recovery of Function; Time Factors; Treatment Outcome

The role of the anti-inflammatory and bronchodilator triple therapy, including a long acting ß2-agonist (LABA), a long-acting muscarinic antagonist (LAMA) and an inhaled corticosteroid (ICS), in the prevention of the exacerbations of chronic obstructive pulmonary disease (COPD) is still not clearly established, and requires comparison with dual therapy (LABA-CSI or LABA-LAMA). IMPACT is a phase 3, double-blind randomized study comparing the tritherapy (LABA-LAMA-ICS) in a single inhaler (vilanterol 25 ?g/umeclidinium 62.5 ?g/fluticasone furoate 100 ?g) with the LABA-ICS association (vilanterol 25 ?g-fluticasone furoate 100 ?g) and the combination LABA-LAMA (vilanterol 25 ?g/umeclidinium 62.5 ?g) on the reduction of the rate of exacerbation as the primary outcome, but also on the pulmonary function, the quality of life, the dyspnea and the mortality.Triple therapy by comparison with dual therapy (LABA-ICS or LABA-LAMA) improves numerous parameters such as the rate of moderate to severe exacerbations, the symptoms, the respiratory function, the quality of life, while being well tolerated. Finally, the IMPACT study gives an "evidence base" for the GOLD guidelines proposing triple therapy in symptomatic COPD patients presenting exacerbations despite dual therapy.. La place de la trithérapie bronchodilatatrice et anti-inflammatoire, comprenant un bêta-2 mimétique à longue durée d’action (LABA), un anticholinergique à longue durée d’action (LAMA) et un corticostéroïde inhalé (CSI), dans la prévention des exacerbations de la bronchopneumopathie chronique obstructive (BPCO) n’est pas encore clairement établie, et nécessite une comparaison avec les associations de LABA-CSI ou les combinaisons LABA-LAMA. IMPACT est une étude randomisée en double aveugle de phase 3 comparant la trithérapie (LABA-LAMA-CSI) en un seul inhalateur (vilantérol 25 ?g/ uméclidinium 62,5 ?g/fluticasone furoate 100 ?g) avec une association LABA-CSI (vilantérol 25 ?g-fluticasone furoate 100 ?g) et une combinaison LABA-LAMA (vilantérol 25 ?g/uméclidinium 62,5 ?g) sur la réduction du taux d’exacerbations comme critère de jugement primaire, mais aussi sur la fonction respiratoire, la qualité de vie, la dyspnée et la mortalité. La trithérapie entraîne une diminution significative du taux d’exacerbations modérées ou sévères, améliore la dyspnée, la fonction respiratoire et la qualité de vie par rapport à l’association fluticasone-vilantérol et la bithérapie bronchodilatatrice uméclidinium-vilantérol chez des patients BPCO symptomatiques et présentant des exacerbations, tout en étant bien tolérée. Finalement, l’étude IMPACT apporte une évidence clinique aux directives du GOLD proposant la trithérapie chez des patients BPCO symptomatiques présentant toujours des exacerbations malgré une bithérapie.

Topics: Androstadienes; Benzyl Alcohols; Chlorobenzenes; Clinical Trials, Phase III as Topic; Drug Combinations; Glucocorticoids; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic

Inhaled corticosteroid/long-acting β-2 agonists (ICS/LABA) combination inhalers have been a lifeline for a generation of chronic obstructive pulmonary disease (COPD) and asthma patients. Fluticasone furoate and Vilanterol (FF/VI) as a once-daily ICS/LABA combination have an extensive clinical trial and real-world data to support its use in COPD patients. Areas covered: The authors provide pharmacological profiles of fluticasone furoate, vilanterol and the FF/VI fixed dose combination. Salient clinical trials evaluating efficacy and safety of the FF/VI combination, and studies demonstrating the impact on COPD exacerbation risk and mortality are also discussed. Expert opinion: ICS/LABA combinations provide bronchodilation and decrease the frequency of COPD exacerbations. Individualizing treatment of each COPD patient based on unique phenotypes will maximize chances of therapeutic responsiveness. Asthma-COPD overlap (ACO), patients with sputum and/or blood eosinophilia, patients with a brisk bronchodilator response, and patients with frequent exacerbations are more likely to show a therapeutic response to ICS than populations who have none of these features. FF/VI will likely remain a popular ICS/LBA combination to treat COPD, as a once-daily inhaled therapy delivered via the Ellipta device popular with COPD patients, with extensive clinical trial and real-world data to support its use.

Topics: Adrenergic beta-2 Receptor Agonists; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive

Randomized clinical trials (RCTs) can be classified as explanatory or pragmatic. Currently, explanatory and pragmatic are considered to be the extremes of a continuum: Many trials have some features of both explanatory and pragmatic RCTs. The Salford Chronic Obstructive Respiratory Disease (COPD) trial was an open-label phase 3 RCT assessing an experimental product (fluticasone furoate-vilanterol) vs usual care. The Salford investigators labelled it as "the world's first phase 3 pragmatic RCT" in COPD patients. The evaluation of the Salford trial by means of the PRECIS-2 tool, yielded a mix of both extremes (explanatory and pragmatic) with several of the 9 domains close to the explanatory extreme and few to the pragmatic one. A number of the features could not be considered as being minimal changes over usual clinical practice. Hence, it would be difficult to accept that the Salford COPD trial was a pragmatic RCT. In addition, all trial participants could have been subject to the Hawthorne effect. The scientific community needs to be rigorous enough when using certain terms related to RCT. It is clear that the Salford COPD trial had particular features-sharing some of explanatory phase 3 RCTs and some of pragmatic RCTs. This, however, is not enough to tag it as a "pragmatic" RCT providing "real-world" data. These words should not be used when referring to prelicensed RCT, unless they really describe how was the trial conducted and the type of data gathered-something that with the current clinical trial regulations will only occur in very rare circumstances.

Topics: Androstadienes; Benzyl Alcohols; Chlorobenzenes; Clinical Trials, Phase III as Topic; Data Accuracy; Drug Combinations; Humans; Pragmatic Clinical Trials as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory System Agents; Terminology as Topic; Treatment Outcome

Topics: Androstadienes; Benzyl Alcohols; Cardiovascular Diseases; Chlorobenzenes; Humans; Pulmonary Disease, Chronic Obstructive; Risk Factors

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Drug Interactions; Humans; Lung; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

This study evaluated patients' experiences with fluticasone furoate/vilanterol (FF/VI) combination therapy in UK patients with asthma or chronic obstructive pulmonary disease (COPD).. Participants aged ≥ 18 years, with self-reported, physician-diagnosed asthma or COPD (≥ 1 year) who had been receiving FF/VI (≥ 3 months) were recruited from UK primary care. This two-phase, mixed-methods study consisted of a semi-structured, telephone-interview phase (qualitative) and a self-completed online/paper-survey phase (quantitative).. The telephone-interview phase included 50 individuals [asthma, n = 25; COPD, n = 25; mean age (SD) 56.7 years (13.3); 50% female]. Of these, 21 with asthma reported that their condition was stable/well controlled and 13 with COPD felt their condition was manageable. Most participants found FF/VI easy to use (asthma, 25; COPD, 23), easy to integrate into their daily routine (asthma, 25; COPD, 24), and able to control symptoms for ≥ 24 h (asthma, 14; COPD, 16). During the survey phase, 199 individuals were recruited [asthma, n = 100; COPD, n = 99; mean age (SD) 63.6 years (15.1); 59.3% female]. Most participants were satisfied/very satisfied with the efficacy of FF/VI in terms of all-day symptom relief (asthma, 84%; COPD, 75%) and found FF/VI easy/very easy to fit into their daily routine (asthma, 99%; COPD, 96%), easy/very easy to use (asthma, 97%; COPD, 92%), and convenient/very convenient to take as instructed (asthma, 95%; COPD, 93%). Significantly more individuals with asthma (87% versus 46%, P < 0.001) and numerically more individuals with COPD (84% versus 76%, P = 0.055) were satisfied/very satisfied with FF/VI compared with their most recent previous maintenance medication.. The majority of individuals in this study had confidence in FF/VI and were satisfied or very satisfied with various key attributes of the treatment.. GSK study HO-15-15503/204888.. GSK.

Topics: Administration, Inhalation; Adult; Aged; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Surveys and Questionnaires; Treatment Outcome

The cost-effectiveness of long-acting muscarinic antagonist (LAMA) umeclidinium bromide (UMEC) 62.5 μg as add-on therapy to other maintenance COPD treatments is unknown.. For the lifetime horizon, compared with FF/VI, FP/SAL and ICS/LABAs, addition of UMEC was associated with incremental costs per quality-adjusted life-years (QALY) of £4050, £7210 and £5780, respectively, and incremental costs per life year gain of £3380, £6020 and £4940. All UMEC-containing regimens resulted in numerically lower exacerbation rates versus comparator regimens over a lifetime horizon.. Addition of UMEC to various ICS/LABA treatments was associated with higher cost than ICS/LABA alone, but was cost-effective in most scenarios.

Topics: Adrenergic beta-2 Receptor Agonists; Androstadienes; Cost-Benefit Analysis; Delayed-Action Preparations; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Humans; Maintenance Chemotherapy; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Chronic obstructive pulmonary disease is associated with a high healthcare resource and cost burden. Healthcare resource utilization was analyzed in patients with symptomatic chronic obstructive pulmonary disease at risk of exacerbations in the FULFIL study. Patients received either once-daily, single inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol) 100 µg/62.5 µg/25 µg or twice-daily dual inhaled corticosteroid/long-acting beta agonist therapy (budesonide/formoterol) 400 µg/12 µg.. FULFIL was a phase III, randomized, double-blind, double-dummy, multicenter study. Unscheduled contacts with healthcare providers were recorded by patients in a daily electronic diary; the costs of healthcare resource utilization were calculated post hoc using UK reference costs.. Over 24 weeks, slightly fewer patients who received fluticasone furoate/umeclidinium/vilanterol (169/911; 18.6%) required contacts with healthcare providers compared with budesonide/formoterol (180/899; 20.0%). Over 52 weeks in an extension population, fewer patients who received fluticasone furoate/umeclidinium/vilanterol required unscheduled contacts with healthcare providers compared with budesonide/formoterol (25.2% vs. 32.7%). Non-drug costs per treated patient per year were lower in the fluticasone furoate/umeclidinium/vilanterol group than the budesonide/formoterol group over 24 and 52 weeks (£653.80 vs. £763.32 and £749.22 vs. £988.03, respectively), with the total annualized cost over 24 weeks being slightly greater for fluticasone furoate/umeclidinium/vilanterol than budesonide/formoterol (£1,289.35 vs. £1,267.45).. This healthcare resource utilization evidence suggests that, in a clinical trial setting over a 24- or 52-week timeframe, non-drug costs associated with management of a single inhaler fluticasone furoate/umeclidinium/vilanterol are lower compared with twice-daily budesonide/formoterol.. ClinicalTrials.gov number: NCT02345161.. GSK.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Androstadienes; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; United Kingdom

Topics: Administration, Inhalation; Aminopyridines; Androstadienes; Asthma; Beclomethasone; Benzamides; Cyclopropanes; Humans; Indans; Maleates; Nasal Sprays; Powders; Pulmonary Disease, Chronic Obstructive; Quinolones; Respiratory Tract Diseases; Rhinitis, Allergic

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Disease Progression; Drug Combinations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive

Topics: Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Dry Powder Inhalers; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive pulmonary disease (COPD) therapies delivered via the ELLIPTA(®) dry powder inhaler across inhalation endpoints representative of the target patient population, using the Electronic Lung (eLung™) to replicate inhaler-specific patient inhalation profiles that were previously recorded in vivo.. Selected profiles, representative of the range of inhalation endpoints achieved by patients with all severities of asthma and COPD, were replicated using the eLung breathing simulator in conjunction with an oropharyngeal cast. A Next Generation Impactor was coupled to the eLung to determine the aerodynamic particle size distribution of the ex-throat dose (ETD) of asthma and COPD therapies delivered via the ELLIPTA inhaler. Delivered dose (DD), ETD, and fine particle dose (FPD; defined as a mass of active substance less than 5 μm) were determined for fluticasone furoate (FF)/vilanterol (VI) 100/25 μg and 200/25 μg (asthma and COPD), umeclidinium (UMEC)/VI 62.5/25 μg (COPD only), FF 100 μg and 200μg monotherapy (asthma only), and UMEC 62.5 μg monotherapy (COPD only).. Inhalation profiles replicated by eLung covered a wide range of peak inspiratory flow rates (41.6-136.9 L/min), pressure drops (1.2-13.8 kPa), and inhaled volumes through the inhaler (0.7-4.2L). DD was consistent across the range of patient representative inhalation parameters for all components (FF, VI, and UMEC) of each therapy assessed; although ETD and FPD were also generally consistent, some small variation was observed. Dose delivery was consistent for each of the components, whether delivered as mono- or combination therapy.. The in vitro performance of the ELLIPTA inhaler has been demonstrated for the delivery of FF/VI, UMEC/VI, FF monotherapy, and UMEC monotherapy. Across a range of inspiratory profiles, DD was consistent, while ETD and FPD showed little flow dependency.

Topics: Administration, Inhalation; Aerosols; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials as Topic; Drug Combinations; Drug Delivery Systems; Dry Powder Inhalers; Equipment Design; Humans; Inhalation; Lung; Models, Anatomic; Models, Biological; Powders; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Severity of Illness Index

The critical role of the combination therapy of an inhaled corticosteroid (ICS) and a long-acting β-adrenoceptor agonist (LABA) in the treatment of patients suffering from asthma and also severe chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations explains why there is a strong interest within the pharmaceutical industry in developing a once-daily ICS/LABA fixed-dose combination (FDC), in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy, and also to overcome the loss of patent protection. GlaxoSmithKline and Theravance have developed an inhaled FDC of the ICS fluticasone furoate (FF) and the LABA vilanterol (VI) as a once-daily treatment for asthma and COPD. FF/VI, by simplifying the dosing schedule, allows, for the first time, a shift from twice-daily to once-daily treatment, with an acceptable safety and tolerability profile that is consistent with the ICS/LABA class. The decision to prescribe FF/VI rather than another ICS/LABA FDC is likely to be based on the patient's preference for the inhaler device, their ability to use the device correctly and the convenience of once-daily dosing frequency as well as comparative costs with other combination products. However, further studies are required to specifically assess these possibilities.

Topics: Androstadienes; Asthma; Benzyl Alcohols; Chlorobenzenes; Drug Administration Schedule; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive

Fluticasone furoate (FF) and mometasone furoate (MF) are potent glucocorticoids recommended for the treatment of allergic rhinitis and other inflammatory diseases. However, whether these drugs render any anti-inflammatory effects in Chronic Obstructive Pulmonary Disease (COPD) is unclear. Emerging data on suppressors of cytokine signaling-3 (SOCS-3) activation in the lungs during inflammation suggests that SOCS3 can be potential targets for regulating pulmonary inflammatory responses in COPD. In this study, we compared the effect of FF with MF on SOCS-3 expression in tobacco smoke (TS) exposed BAEpCs in vitro and in a mouse model of COPD in vivo. BAEpCs were exposed to TS or room air and later were treated with either FF (1nmol-100nmol) or MF (10-500nmol) inhibitors in the presence and absence of Jak1 and Stat-3 inhibitors. C57BL/6 mice were exposed to TS for 6 months, and treated with either FF, MF for 2 and 4 weeks. FF induced 7 fold increases in SOCS-3 expression in BAEpCs whereas MF induced a three fold increase when compared to control. Jak1 and Stat-3 inhibitors significantly inhibited the FF and MF induced SOCS-3 expression in BAEpCs. In addition, FF and MF restored TS inhibited SOCS-3 expression in the airway epithelium of COPD mice. FF and MF treatments significantly reduced leukocyte infiltration in airways and inhibited lung inflammation. Our study elucidates a novel mechanism for the anti-inflammatory action of FF in COPD. The superior efficacy of FF may be in part due to the increased expression of SOCS-3 in BAEpCs.

Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Bronchi; Cells, Cultured; Epithelial Cells; Glucocorticoids; Humans; Janus Kinase 1; Mice; Mice, Inbred C57BL; Mometasone Furoate; Pregnadienediols; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Tobacco Smoke Pollution

▼Relvar Ellipta 92 μg/22 μg (GSK) is a dry powder inhaler that contains a corticosteroid (fluticasone furoate) and a long-acting beta2 agonist (vilanterol trifenatate).1 Neither ingredient is currently marketed as a single-ingredient inhalation product, although fluticasone furoate is available as a nasal spray for the treatment of allergic rhinitis. Relvar Ellipta 92 μg/22 μg is licensed for once-daily use as maintenance therapy for chronic obstructive pulmonary disease (COPD) and asthma. In this article we consider the evidence for its use in the management of patients with COPD. An article in a future issue will review its use in the management of patients with asthma.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Drug Combinations; Dry Powder Inhalers; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Approval; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; United States

Currently available glucocorticoids are relatively short acting and may be less effective in patients with chronic obstructive pulmonary disease (COPD) where high levels of oxidative stress are seen. Here we show that a novel glucocorticoid, fluticasone furoate (FF), has a longer duration of action in several cell systems compared with fluticasone propionate (FP) and budesonide, and unlike FP, FF is resistant to oxidative stress. FF had similar or slightly higher potency to FP and was 2-9 fold more potent than budesonide, when assessed at 4h, in inhibiting inflammatory cytokine production in epithelial cell lines (BEAS2B, A549), primary bronchial epithelial cells and a monocytic cell line (U937). The potency of FF was sustained beyond 16 h with or without washout compared with FP or budesonide, such that it showed a greater duration of action in this range of cellular assays. The activated YFP-conjugated glucocorticoid receptor was detectable in nuclei of FF treated BEAS2B cells for at least for 30 h, and FF had a longer duration of action than FP in inhibiting activation of transcription factors such as NF-κB and AP-1. In addition, FF showed superior effects to FP in peripheral blood mononuclear cells from patients with COPD and also in U937 cells or primary bronchial epithelial cells under conditions of oxidative stress. The longer duration of action and oxidative stress insensitivity of FF compared with FP has potential clinical implications for the control of inflammation in respiratory diseases, such as COPD.

Topics: Active Transport, Cell Nucleus; Androstadienes; Asthma; Budesonide; Cell Line; Cell Nucleus; Fluticasone; Glucocorticoids; Humans; Leukocytes, Mononuclear; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Respiratory System; Time Factors; Transcription Factor RelA