gsk573719 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

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Dyspnea; Forced Expiratory Volume; Glycopyrrolate; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Maintenance bronchodilator therapy with long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is the cornerstone treatment for patients with stable chronic obstructive pulmonary disease (COPD). Fixed-dose combinations (FDCs) of LABA/LAMA are recommended for the majority of symptomatic COPD patients by global guidelines; regional guidelines such as the Japanese and Korean guidelines also provide similar recommendations for the use of LABA/LAMA FDCs. This review comprehensively describes the latest clinical evidence from key studies on the efficacy and safety of four approved LABA/LAMA fixed-dose combinations: indacaterol/glycopyrronium, vilanterol/umeclidinium, formoterol/aclidinium, and olodaterol/tiotropium. Additionally, in this review we describe the rationale behind the use of LABA/LAMA FDC therapy, key findings from the preclinical and clinical trial evaluation of respective LABA and LAMA monocomponents, and the efficacy and safety of LABA/LAMA FDCs. Special emphasis is placed on the clinical evidence for the monocomponents and LABA/LAMA FDCs from the Asian population. This detailed overview of the efficacy and safety of LABA/LAMA FDCs in global and Asian COPD patients is envisaged to provide a better understanding of the benefits of these therapies and to inform healthcare providers and patients on their appropriate use.Funding: Novartis Pharma K.K.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Asian People; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Tiotropium Bromide; Treatment Outcome; Tropanes

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Dry Powder Inhalers; Evidence-Based Medicine; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Recovery of Function; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is predicted to be one of the leading causes of death worldwide. Pharmacologic treatment options of COPD are bronchodilators, using either long-acting β2-agonists (LABAs), or long-acting muscarinic antagonists (LAMAs), or a combination of two. Anoro Ellipta (umeclidinium + vilanterol) dry powder inhaler, a fixed-dose combination of LAMA and LABA, was Food and Drug Administration (FDA) approved in 2013 for COPD. The objective of this study is to evaluate the efficacy and safety of once daily umeclidinium/vilanterol (62.5 mcg/25 mcg) in COPD patients, focusing on pharmacodynamic and pharmacokinetic characteristics, efficacy and safety in clinical studies and cost. Literature search was done through PubMed (2004-2017) using the terms umeclidinium, vilanterol, COPD, LABA and LAMA. Recent and significant clinical trials about the monocomponents and their combination were identified, in addition to reviews, guidelines for COPD, data from manufacturer and FDA product labels. The search was limited to English language studies on human subjects. Clinical data published on the combination of umeclidinium/vilanterol in patients with COPD have shown greater improvements in lung function compared to monotherapies. However, further studies comparing umeclidinium/vilanterol FDC (ANORO) to other LABA/LAMA combinations are needed.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dry Powder Inhalers; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Respiratory Function Tests

Recent updates to the GOLD guidelines emphasize the use of combination LABA and LAMA bronchodilators for patients with chronic obstructive pulmonary disease with persistent dyspnea despite monotherapy or frequent exacerbations despite LAMA monotherapy. There are several commercially available LABA/LAMA fixed dose combination inhalers, which are likely to become the principle therapy for many patients with COPD.. In the last 4 years, there have been a number of large clinical trials evaluating the efficacy and safety of combined LAMA and LABA bronchodilators. LAMA/LABA fixed dose combination therapies have consistently demonstrated clinically significant improvements to airway obstruction, dyspnea, and quality of life whenever compared with placebo, and more modest improvements compared with bronchodilator monotherapies and combined bronchodilator/inhaled corticosteroid therapy.. New guidelines emphasize combination bronchodilators as a mainstay of therapy for many patients with symptomatic COPD and there are several new combination bronchodilator therapies available to patients. It is important for physicians and patients to understand the range and degree of expected clinical effects and the safety profiles of these new medications.

Topics: Administration, Inhalation; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Tiotropium Bromide; Tropanes

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

People with chronic obstructive pulmonary disease (COPD) have poor quality of life, reduced survival, and accelerated decline in lung function, especially associated with acute exacerbations, leading to high healthcare costs. Long-acting bronchodilators are the mainstay of treatment for symptomatic improvement, and umeclidinium is one of the new long-acting muscarinic antagonists approved for treatment of patients with stable COPD.. To assess the efficacy and safety of umeclidinium bromide versus placebo for people with stable COPD.. We searched the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, the World Health Organization (WHO) trials portal, and the GlaxoSmithKline (GSK) Clinical Study Register, using prespecified terms, as well as the reference lists of all identified studies. Searches are current to April 2017.. We included randomised controlled trials (RCTs) of parallel design comparing umeclidinium bromide versus placebo in people with COPD, for at least 12 weeks.. We used standard Cochrane methodological procedures. If we noted significant heterogeneity in the meta-analyses, we subgrouped studies by umeclidinium dose.. We included four studies of 12 to 52 weeks' duration, involving 3798 participants with COPD. Mean age of participants ranged from 60.1 to 64.6 years; most were males with baseline mean smoking pack-years of 39.2 to 52.3. They had moderate to severe COPD and baseline mean post-bronchodilator forced expiratory volume in one second (FEV. Umeclidinium reduced acute exacerbations requiring steroids, antibiotics, or both, although no evidence suggests that it decreased the risk of hospital admission due to exacerbations. Moreover, umeclidinium demonstrated significant improvement in quality of life, lung function, and symptoms, along with lesser use of rescue medications. Studies reported no differences in adverse events, non-fatal serious adverse events, or mortality between umeclidinium and placebo groups; however, larger studies would yield a more precise estimate for these outcomes.

Topics: Anti-Bacterial Agents; Bromides; Disease Progression; Female; Forced Expiratory Volume; Hospitalization; Humans; Male; Middle Aged; Numbers Needed To Treat; Placebos; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Randomized Controlled Trials as Topic; Smoking; Steroids

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; 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

A number of new agents for the management of chronic obstructive pulmonary disease (COPD) are at different stages of development, including several inhaled long-acting antimuscarinics (LAMA). Long-acting bronchodilators are considered to be central to the management of COPD due to the evidence supporting their efficacy and safety. Umeclidinium, a LAMA, has recently been approved for the maintenance treatment of moderate to very severe COPD in a number of countries. This comprehensive review and pooled meta-analysis provides detailed information about the efficacy and safety of this agent. The pharmacokinetics and pharmacodynamics of umeclidinium observed in phase I and II studies support its once-daily administration. Umeclidinium is rapidly cleared from blood, and renal or hepatic impairment do not lead to significant changes in drug disposition. A pooled analysis of phase III and comparative studies of umeclidinium in patients with moderate to very severe COPD showed significant improvement in lung function measures, including trough forced expiratory volume in 1 s (FEV1), as well as in acute exacerbations of COPD, dyspnea, and quality of life. Adverse effects, including known anticholinergic effects, were uncommon with umeclidinium. Limited data suggest the efficacy of umeclidinium is similar to that of tiotropium. Umeclidinium is administered as a dry powder inhaler, provides adequate lung delivery in patients with moderate to very severe airflow obstruction, and appears to be easily used by patients. Umeclidinium provides a safe and effective option as an inhaled LAMA for the management of COPD.

Topics: Administration, Inhalation; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Dry Powder Inhalers; Muscarinic Antagonists; Muscle Tonus; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Several new fixed-dose combination bronchodilators have been launched in the world, and 3 different types are now available in Japan. Assessing their efficacy relative to each other has not been performed yet. In the present manuscript, characteristics of glycopyrronium/indacaterol, umeclidinium/vilanterol and tiotropium/olodaterol were reviewed. In particular, changes in trough and peak forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, and transitional dyspnea index (TDI) focal scores were reviewed in these bronchodilators.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Respiratory Function Tests; Tiotropium Bromide; Treatment Outcome

The role of umeclidinium plus vilanterol as a combination therapy for chronic obstructive pulmonary disease (COPD) has not yet been clearly defined.. The aim of this meta-analysis was to evaluate the efficacy and safety of umeclidinium plus vilanterol, in contrast to either monotherapy or placebo.. Systematic searches were conducted in Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and the Chinese Biomedical Literature Database (CBM). Randomized clinical trials pertaining to the treatment of COPD with the combination of umeclidinium and vilanterol, versus umeclidinium, vilanterol or placebo, were reviewed. Studies were pooled to mean differences (MDs), with 95 % confidence intervals (CIs).. Six studies were included in our meta-analysis. The application of umeclidinium plus vilanterol compared with umeclidinium alone showed increases in trough forced expiratory volume in 1 s [FEV. Compared with the other three groups, i.e. placebo, umeclidinium and vilanterol, umeclidinium plus vilanterol improves lung function and quality of life in patients with COPD, reduces the use of albuterol, and does not increase the incidence of adverse events and serious adverse events.

Topics: Albuterol; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Randomized Controlled Trials as Topic

A solid scientific rationale and an increasing body of clinical evidence fully support the use of an antimuscarinic agent combined with a β-agonist in chronic obstructive pulmonary disease. In this article, we focus on the development of an inhaled fixed dose combination (FDC) of two 24-h bronchodilators, umeclidinium bromide and vilanterol (UMEC/VI) (ANORO). Several pivotal clinical trials have documented the impact of this combination on lung function and other outcome measures such as quality of life, dyspnea, rescue medication use and exercise capacity, with no clinically meaningful treatment-related changes in vital signs or clinical laboratory parameters. These results allow us to predict that UMEC/VI will have a role in the maintenance treatment of chronic obstructive pulmonary disease. It remains to determine its impact on exacerbations. In any case, trials comparing UMEC/VI with other dual bronchodilator FDCs, and also with inhaled corticosteroid/long-acting β-agonist FDCs, are needed to assess the advantages, if any, of UMEC/VI FDC over other therapies.

Topics: Benzyl Alcohols; Bromides; Bronchodilator Agents; Chlorobenzenes; Clinical Trials as Topic; Double-Blind Method; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic

Umeclidinium/vilanterol (Anoro(®) Ellipta™; Laventair™) is an inhaled fixed-dose combination of a long-acting muscarinic receptor antagonist and a long-acting β2-adrenoceptor agonist. It is available in several countries, including Japan, the USA, Canada and those of the EU, where it is indicated for oral inhalation in adults with chronic obstructive pulmonary disease (COPD). Umeclidinium/vilanterol is administered once daily using the Ellipta™ multi-dose dry powder inhaler, which is regarded as easy to use. Umeclidinium/vilanterol (62.5/25 µg once daily, equivalent to a delivered dose of 55/22 µg once daily) was effective and well tolerated in adult patients with COPD participating in large, multicentre trials of up to 24 weeks' duration. Umeclidinium/vilanterol improved pulmonary function to a significantly greater extent than placebo and each of the individual components. Moreover, umeclidinium/vilanterol was significantly more effective than once-daily tiotropium bromide monotherapy and a twice-daily fixed combination of salmeterol/fluticasone propionate at improving pulmonary function. Umeclidinium/vilanterol also had beneficial effects on dyspnoea, use of rescue medication, exacerbations, health-related quality of life and, in one study, exercise endurance. Umeclidinium/vilanterol is generally well tolerated in patients with COPD, with the most common adverse events in clinical trials being headache and nasopharyngitis. Umeclidinium/vilanterol was not associated with a clinically relevant increased risk of cardiovascular adverse events in patients with COPD, when data from several clinical trials were pooled. Thus, inhaled umeclidinium/vilanterol extends the treatment options currently available for the maintenance treatment of adults with COPD and has the convenience of once-daily administration.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Umeclidinium bromide (UM) with vilanterol (VI) is the first once-daily long-acting muscarinic antagonist/long-acting β2 agonist (LAMA/LABA) combination approved for use in the treatment of chronic obstructive pulmonary disease (COPD) in the USA. Prior to this, only combinations of short-acting bronchodilators and short-acting muscarinic antagonists were available in the USA as a single inhaler and they required frequent dosing. LAMA or LABA therapy is the recommended first choice for moderate-to-very severe COPD with combination therapy added if monotherapy fails to control patients' symptoms. This allows lower dosing of individual medications, which may limit adverse effects. It could also have the additional benefit of improving patient compliance by making medication regimens less laboring.. A comprehensive literature search of journal articles and abstracts looking for trials that evaluated both the efficacy and the safety of UM/VI revealed that UM/VI improves patients' lung function and overall health status, while maintaining excellent safety and tolerability profiles compared to placebo and other bronchodilators.. Given the clinical efficacy, favorable safety profile and ease of use, clinicians may recommend UM/VI to patients with moderate-to-very severe COPD - a shift that could have significant impact on the management of COPD.

Topics: Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Humans; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Quinuclidines

COPD guidelines recommend the combined use of inhaled long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) if symptoms are not improved by a single agent. This systematic review tested the hypothesis that the bronchodilator effect of the LABA/LAMA combination, umeclidinium (UMEC)/vilanterol (VIL), would translate into better outcomes without incurring increased adverse events (AEs).. This was a systematic review of randomized, placebo-controlled or crossover trials (> 4 weeks) involving UMEC/VIL compared with its monocomponents, tiotropium, or fluticasone/salmeterol. Primary outcomes were trough FEV1, serious adverse events (SAEs), and serious cardiovascular events (SCVEs).. Eleven trials from 10 studies (9,609 patients) showed that UMEV/VIL provided superior improvements in lung function compared with UMEC, VIL, tiotropium, and fluticasone propionate/salmeterol (mean trough FEV1, 60, 110, 90, and 90 mL, respectively; P < .0001). Also, UMEC/VIL had a greater likelihood of demonstrating a minimal clinically important difference on the Transition Dyspnea Index compared with UMEC and VIL (number needed to treat for benefit [NNTB] = 14 and 10, respectively). UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB = 42 and 41, respectively). On the contrary, we noted no significant differences between UMEC/VIL and tiotropium with respect to dyspnea, health status, or risk of COPD exacerbation. Regarding safety issues, the incidence of AEs, SAEs, SCVEs, and mortality on treatment was similar across treatments, suggesting reduced safety concerns with the use of the UMEC/VIL combination.. Once-daily inhaled UMEC/VIL showed superior efficacy compared with its monocomponents, tiotropium, and fluticasone/combination in patients with moderate to severe COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Animals; Cholinergic Antagonists; Clinical Trials as Topic; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

The purpose of this review is to discuss the cardiovascular risk associated with inhaled anticholinergics in chronic obstructive pulmonary disease. Several meta-analyses of data for tiotropium raised the possibility of an increased risk for arrhythmia, angina, myocardial infarction, etc. This review includes the data of retrospective studies of databases using databases, randomized controlled trials, and meta-analyses of clinical trials. The conclusions of studies were inconsistent. In most clinical trials the incidence of cardiovascular adverse events was similar in active treatment and placebo groups, especially in patients with previous cardiovascular diseases. Considering meta-analyses, there is little, if any, evidence for the association between anticholinergics and the development of cardiovascular symptoms. The author discusses the presence and function of cholinergic receptor subtypes in human heart, and cardiac functions controlled by the autonomic nervous system via these receptors, their possible role, and pharmacokinetic properties of inhaled anticholinergics. The author concludes that it is not possible to find evidence of increased cardiovascular harm of inhaled anticholinergics.

Topics: Administration, Inhalation; Bronchodilator Agents; Cardiovascular Diseases; Cardiovascular System; Cholinergic Antagonists; Clinical Trials as Topic; Glycopyrrolate; Humans; Incidence; Ipratropium; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide

Randomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative efficacy of tiotropium 18 µg once-daily (OD) and newer agents (aclidinium 400 µg twice-daily, glycopyrronium 50 µg OD, and umeclidinium 62.5 µg OD).. A systematic literature review identified randomized, controlled trials of adult COPD patients receiving LAMAs. A NMA within a Bayesian framework examined change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnea index focal score, St George's Respiratory Questionnaire score, and rescue medication use.. Twenty-four studies (n=21,311) compared LAMAs with placebo/each other. Aclidinium, glycopyrronium, tiotropium, and umeclidinium, respectively, demonstrated favorable results versus placebo, for change from baseline (95% credible interval) in 12-week trough FEV1 (primary endpoint: 101.40 mL [77.06-125.60]; 117.20 mL [104.50-129.90]; 114.10 mL [103.10-125.20]; 136.70 mL [104.20-169.20]); 24-week trough FEV1 (128.10 mL [84.10-172.00]; 135.80 mL [123.10-148.30]; 106.40 mL [95.45-117.30]; 115.00 mL [74.51-155.30]); 24-week St George's Respiratory Questionnaire score (-4.60 [-6.76 to -2.54]; -3.14 [-3.83 to -2.45]; -2.43 [-2.92 to -1.93]; -4.69 [-7.05 to -2.31]); 24-week transitional dyspnea index score (1.00 [0.41-1.59]; 1.01 [0.79-1.22]; 0.82 [0.62-1.02]; 1.00 [0.49-1.51]); and 24-week rescue medication use (data not available; -0.41 puffs/day [-0.62 to -0.20]; -0.52 puffs/day [-0.74 to -0.30]; -0.30 puffs/day [-0.81 to 0.21]). For 12-week trough FEV1, differences in change from baseline (95% credible interval) were -12.8 mL (-39.39 to 13.93), aclidinium versus tiotropium; 3.08 mL (-7.58 to 13.69), glycopyrronium versus tiotropium; 22.58 mL (-11.58 to 56.97), umeclidinium versus tiotropium; 15.90 mL (-11.60 to 43.15), glycopyrronium versus aclidinium; 35.40 mL (-5.06 to 76.07), umeclidinium versus aclidinium; and 19.50 mL (-15.30 to 54.38), umeclidinium versus glycopyrronium. Limitations included inhaler-related factors and safety; longer-term outcomes were not considered.. The new LAMAs studied had at least comparable efficacy to tiotropium, the established class standard. Choice should depend on physician's and patient's preference.

Topics: Aged; Bayes Theorem; Bronchodilator Agents; Drug Administration Schedule; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Recovery of Function; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

Testing the new combined bronchodilator Anoro Ellipta in different clinical trials gives to its high clinical efficacy and safety in chronic obstructive pulmonary disease. The drug contains the molecules of sustained-release selective β2-adrenergic receptor agonist (vilanterol) and a muscarinic cholinergic receptor antagonist (umeclidinium bromide). The bronchodilating mechanisms of umeclidinium bromide are in the competitive inhibition of the binding of acetylcholine with muscarinic acetylcholine receptors of airway smooth muscles whereas in those of vilanterol are in that with the stimulation of intracellular adenylate cyclase. On days 1 and 24 after inhalation of the first dose of vilanterol and umeclidinium bromide, there was a significant increase in the forced expiratory volume in one second as compared to placebo. No clinical effects on QT interval on an electrocardiogram and cardiac rhythm were found. The benefits of an inhalation device (Ellipta) are its innovation design ensuring the effective delivery of an aerosol dose into the airway, convenience, and simplicity.. При изучении нового комбинированного бронходилататора Аноро Эллипта в различных клинических испытаниях доказаны его высокая клиническая эффективность и безопасность при хронической обструктивной болезни легких. В состав препарата входят молекулы селективного агониста β2-адренергических рецепторов длительного действия (вилантерол) и антагониста мускариновых холинорецепторов (умеклидиния бромид). Механизмы бронходилатации под действием умеклидиния бромид заключаются в конкурентном ингибировании связывания ацетилхолина с мускариновыми ацетилхолиновыми рецепторами гладкой мускулатуры дыхательных путей, тогда как у вилантерола - со стимуляцией внутриклеточной аденилатциклазы. Продемонстрировано достоверное увеличение по сравнению с плацебо объема форсированного выдоха за 1-ю секунду (ОФВ1) после ингаляции первой дозы вилантерола и умеклидиния бромид в 1-й день и на 24-е сутки. Клинически значимых влияний на интервал QT на электрокардиограмме и ритм сердца не обнаружено. Преимуществами ингаляционного устройства (Эллипта) являются инновационная конструкция, обеспечивающая эффективную доставку дозы аэрозоля в дыхательные пути, удобство и простота ухода.

Topics: Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Administration, Inhalation; Animals; Benzyl Alcohols; Chlorobenzenes; Cholinergic Antagonists; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic

Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting β2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and convenient treatment option in COPD. This review summarizes published efficacy and safety data from clinical trials of both LABA/LAMA and novel LABA/ICS combinations in patients with COPD.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Disease Management; Disease Progression; Drug Combinations; Ethanolamines; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Drugs from the two major classes of bronchodilator; umeclidinium, a long-acting muscarinic antagonist (LAMA), and vilanterol, a long-acting β2 agonist (LABA), have been combined in a single inhaler device for once-daily use in chronic obstructive pulmonary disease (COPD). These drugs have been proven safe and well tolerated in patients with COPD and show an enhanced improvement in FEV1 when compared to either drug in isolation and when compared with an established LAMA drug. In this article, we discuss the data supporting this combination inhaler and also review alternative combined LAMA/LABA options. We discuss where these agents are likely to find a place in the current therapy of COPD and where the future is likely to lead with these and other therapies.

Topics: Administration, Inhalation; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. Bronchodilator therapy is the cornerstone in COPD treatment. Bronchodilation in COPD is mainly achieved via administration of long- and ultralong-acting β2-agonists and with long-acting muscarinic antagonists. New combinations of bronchodilators with dual-acting muscarinic antagonist and β2-agonist properties have been licensed, and others are currently being developed with the aim of achieving once-daily dosing, and therefore may improve the likelihood of treatment compliance. These combination bronchodilators include glycopyrronium bromide/indacaterol maleate, umeclidinium (UMEC) bromide/vilanterol trifenatate (VI), aclidinium bromide/formoterol and tiotropium bromide/olodaterol (Boehringer Ingelheim, Germany). This review will focus mainly on studies and clinical trials involving the novel fixed-dose combination of UMEC/VI at doses of 125/25 μg and 62.5/25 μg in patients with COPD. Data from large clinical trials involving more than 4,500 COPD patients indicate that UMEC/VI is an effective once-daily treatment in COPD with improved pulmonary function. Future studies assessing the impact of this combination on exacerbations, delay in disease progression, and health status in patients with COPD are warranted.

Topics: Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Recovery of Function; Time Factors; Treatment Outcome

Umeclidinium (UMEC) is a long-acting inhaled antagonist of muscarinic cholinergic receptors. The FDA approved UMEC for maintenance treatment of chronic obstructive pulmonary disease (COPD) in 2013 and it became available for commercial use as a single agent in 2014. After tiotropium, this is the only other once daily LAMA available for COPD patients.. In this article, we have comprehensively reviewed the pharmacokinetic properties and analyzed the currently available randomized controlled trials on the efficacy and safety profile of UMEC. We have discussed the current clinical application of UMEC and its future implication.. UMEC is the newer long-acting antimuscarinic agent (LAMA) that has demonstrated significant improvement in lung function and improved the quality of life in moderate-to-severe COPD patients. It is suitable for once daily dosing, has low anticholinergic side effects and is well tolerated. Overall, it is a safe, effective and convenient LAMA for maintenance therapy in COPD patients.

Topics: Administration, Inhalation; Animals; Drug Administration Schedule; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Risk Assessment; Risk Factors; Treatment Outcome

Umeclidinium is a novel inhaled long-acting muscarinic receptor antagonist (LAMA) approved for treatment of chronic obstructive pulmonary disease (COPD). It provides a bronchodilation of at least 24 h, is well tolerated and has a safe profile. In this article, we describe its pharmacokinetic and pharmacodynamic characteristics. Moreover, we present a meta-analysis of randomized clinical trials carried out in COPD patients, in which the change of forced expiratory volume in 1 s (FEV1) induced by umeclidinium has been compared with that elicited by placebo or the active compound tiotropium. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the Ellipta™ inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could to be used as an alternative to LAMAs already in the market, although substantial information is still lacking. It is likely that in the future, umeclidinium will be used frequently, mainly in combination with vilanterol, which is a new once-daily long-acting β2-agonist (LABA).

Topics: Bronchodilator Agents; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

The defining feature of chronic obstructive pulmonary disease (COPD) is progressive airflow limitation that causes air trapping and hyperinflation. The increasing hyperinflation results in dyspnea along with associated inability to engage in the activities of daily living. The American Thoracic Society (ATS), European Respiratory Society (ERS) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) treatment guidelines all place bronchodilators as the foundation of pharmacological management of COPD. In patients with moderate-to-very-severe respiratory impairment, adding regular treatment with one or more long-acting bronchodilators is recommended [long-acting β2-agonists (LABAs) or long-acting muscarinic antagonists (LAMAs)]. A growing body of evidence shows that LAMA and LABA co-administration is more effective than either drug class alone in managing stable COPD to improve lung function, symptoms and health status. Recently, new drug applications (NDAs) for a fixed-dose combination (FDC) of umeclidinium (UMEC), a LAMA, and vilanterol (VI), a LABA, at UMEC/VI doses of 125/25 and 62.5/25 µg have been submitted by sponsors to the US Food and Drug Administration (FDA) and to the European Medicines Agency (EMA). Thus, UMEC/VI has become the first FDC LAMA/LABA product that has reached a regulatory approval stage. Other LAMA/LABA once-daily combinations coming through development include FDCs of tiotropium and olodaterol, glycopyrronium and indacaterol, and twice-daily aclidinium and formoterol. The aim of this review is to explore currently available data for once-daily UMEC/VI in the context of the evolving standards of COPD management.

Topics: Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Dose-Response Relationship, Drug; Drug Combinations; Humans; Muscarinic Antagonists; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Severity of Illness Index

An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Quinuclidines

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

In chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs-glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)-in patients with COPD.. We enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC).. No significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported.. The three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported. Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020).

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzoxazines; Cross-Over Studies; Disease Progression; Drug Administration Schedule; Drug Combinations; Female; Forced Expiratory Volume; Humans; Japan; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide; Treatment Outcome

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

Exacerbations account for the greatest proportion of costs associated with chronic obstructive pulmonary disease (COPD). Here we aimed to evaluate, from the US payer perspective, the costs associated with moderate and severe COPD exacerbation events for patients treated with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) compared with FF/VI or UMEC/VI.. This post hoc, within-trial economic analysis used data derived from the InforMing the PAthway of COPD Treatment (IMPACT) study (NCT02164513).. Treatment groups within the IMPACT trial received either triple therapy with FF/UMEC/VI (100/62.5/25 mcg) or dual therapy (FF/VI [100/25 mcg] or UMEC/VI [62.5/25 mcg]). The primary end point for this IMPACT post hoc analysis was cost differences between the treatment arms related to 1-year on-treatment combined moderate and severe COPD exacerbation events.. The final study sample for this within-trial analysis consisted of 10,355 patients, 49% of whom experienced an on-treatment moderate or severe exacerbation during the study. The mean 1-year on-treatment cost estimate associated with combined moderate and severe exacerbations was highest with UMEC/VI and lowest with FF/UMEC/VI ($6205 vs $4913, respectively). Mean cost differences were statistically significant for all pairwise comparisons of FF/UMEC/VI with FF/VI or UMEC/VI (-$549 [95% CI, -$565 to -$533] and -$1292 [95% CI, -$1313 to -$1272], respectively; both P <.0001).. Treatment with FF/UMEC/VI compared with FF/VI or UMEC/VI in the US healthcare system resulted in lower exacerbation-related costs for combined moderate/severe exacerbation events, as well as moderate and severe exacerbations separately.

Topics: Administration, Inhalation; Adult; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Respiratory Function Tests; Severity of Illness Index

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

LABA (long-acting β2-agonists) and/or LAMA (long-acting muscarinic antagonists) represent the first treatment options for patients with symptomatic COPD. Although both display different mechanisms of activity, in combination they have a stronger broncho-dilating effect than monotherapy; hence, a combination of both LABA and LAMA is particularly recommended for patients whose symptoms cannot be sufficiently improved by a single active ingredient. To date, only few data have been collected regarding the therapeutic outcomes of approved LABA/LAMA fixed-dose combinations (FDCs) under everyday (real-life) conditions in non-clinical trial settings.. The main objective of the DETECT study was to investigate the impact of aclidinium/formoterol (AB/FF, b.i.d.), glycopyrronium/indacaterol (GLY/IND, q.d.) and umeclidinium/vilanterol (UME/VL, q.d.) in patients with COPD in daily clinical practice. Therefore, a prospective, non-randomized, 12-month, observational study was implemented to assess the effectiveness of these treatments in patients who had been switched to FDC within the last 3 months or for whom such a changeover was intended. Changes in lung function were analyzed by the forced expiratory volume (FEV1) and forced vital capacity (FVC) measures. Quality of life and well-being were evaluated by the COPD Assessment Test (CAT™). Furthermore, a number of exacerbations and early morning COPD symptoms were documented.. In total, 3653 patients were enrolled. FEV1 and FVC values significantly improved during the study with AB/FF (increase by 0.09 ± 0.40 L and 0.10 ± 0.57 L, respectively; p<0.0001), GLY/IND (0.06±0.38/0.05±0.51 L; p<0.0001 and p=0.0025) and UME/VL (0.12±0.39/0.10±0.52 L; p<0.0001). CAT scores decreased indicating improved COPD (AB/FF, 4.17±8.30; GLY/IND, 3.66±7.88; UME/VL, 4.06±7.96; p<0.0001). Moreover, the number of exacerbations as well as early morning COPD symptoms similarly diminished in all treatment groups. A comparable proportion of patients with adverse drug reactions was recorded: AB/FF, 4.07% of patients; GLY/IND, 3.52%; UME/VL, 3.64%.. In summary, AB/FF, GLY/IND and UME/VL provided clinical benefits in lung function, quality of life and early morning COPD symptoms in a broad cohort of COPD patients under routine medical practice conditions. All three treatments were well tolerated.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Quinuclidines; Treatment Outcome

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

Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids.. The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV. Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

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

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

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

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

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Airway Resistance; Albuterol; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cholinergic Antagonists; Cross-Over Studies; Double-Blind Method; Dyspnea; Electromyography; Female; Humans; Inhalation; Male; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Respiratory Function Tests; Respiratory Muscles; Spirometry

Directly recorded patient experience of symptoms and health-related quality of life (HRQoL) can complement lung function and exacerbation rate data in chronic obstructive pulmonary disease (COPD) clinical studies. The FULFIL study recorded daily symptoms and activity limitation together with additional patient-reported outcomes of dyspnea and HRQoL, as part of the prespecified analyses. FULFIL co-primary endpoint data have been previously reported.. FF/UMEC/VI showed greater reductions from baseline in 4-weekly mean E-RS: COPD total and all subscale scores compared with BUD/FOR; differences were statistically significant (P < 0.05) at each time period. FF/UMEC/VI also demonstrated greater improvements from baseline at weeks 4 and 24 in SGRQ domain scores and TDI focal score compared with BUD/FOR. At weeks 4 and 24, improvements greater than the minimal clinically important difference from baseline were observed in CAT score with FF/UMEC/VI, but not BUD/FOR; differences were statistically significant (P ≤ 0.003).. These findings demonstrate sustained daily symptom and HRQoL benefits of FF/UMEC/VI versus BUD/FOR. The inclusion of the CAT may provide data that are readily generalizable to everyday clinical practice.. ClinicalTrials.gov number: NCT02345161.. GSK.

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

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

Time restricted feeding decreases energy intake without calorie counting and may be a viable option for weight loss. However, the effect of this diet on body weight in obese subjects has never been examined.. This study investigated the effects of 8-h time restricted feeding on body weight and metabolic disease risk factors in obese adults.. Body weight and energy intake decreased in the time restricted group (-2.6% ± 0.5; -341 ± 53 kcal/d) relative to controls over 12 weeks (. These findings suggest that 8-h time restricted feeding produces mild caloric restriction and weight loss, without calorie counting. It may also offer clinical benefits by reducing blood pressure.

Topics: Adult; Age Factors; Aged; B-Lymphocytes; Benzyl Alcohols; Blood Cells; Bronchodilator Agents; Chlorobenzenes; Cross-Over Studies; Disease Progression; Drug Combinations; Female; Flow Cytometry; Forced Expiratory Volume; Humans; Immunophenotyping; Liver Cirrhosis, Biliary; Lymphocyte Activation; Male; Middle Aged; Pruritus; Pulmonary Disease, Chronic Obstructive; Quinuclidines; T-Lymphocytes, Regulatory; Th17 Cells; Treatment Outcome

Topics: Adult; Aged; Benzyl Alcohols; Chlorobenzenes; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Switzerland

UMEC/VI was associated with small improvements in QALYs (+ 0.029) over a 3-year time horizon, compared with TIO/OLO, alongside cost savings of €393/patient. The ITT scenario analysis and sensitivity analyses had similar results. All probabilistic simulations resulted in UMEC/VI being less costly and more effective than TIO/OLO.

Topics: Aged; Benzoxazines; Benzyl Alcohols; Chlorobenzenes; Cost-Benefit Analysis; Cross-Over Studies; Drug Combinations; Female; Humans; Male; Middle Aged; National Health Programs; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Single-Blind Method; Spain; Tiotropium Bromide

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

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

To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI).. Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 μg and once-daily UMEC/VI 62.5/25 μg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV. IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).

Topics: Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cross-Over Studies; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Severity of Illness Index

Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease (COPD). In two 12-week, double-blind, parallel-group studies, patients with COPD were randomized 1:1:1 to once-daily umeclidinium (UMEC; 62.5 μg and 125 μg) or placebo (PBO), added to twice-daily fluticasone propionate/salmeterol (FP/SAL; 250/50 μg). In both studies, the primary efficacy measure was trough forced expiratory volume in 1 second (FEV1) at Day 85. Secondary endpoints were weighted-mean (WM) FEV1 over 0-6 hours post-dose (Day 84) and rescue albuterol use. Health-related quality of life outcomes (St. George's Respiratory Questionnaire [SGRQ] and COPD assessment test [CAT]) were also examined. Safety was assessed throughout. Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV1 (Day 85: 0.127-0.148 L) versus PBO+FP/SAL. Similarly, both UMEC+FP/SAL doses provided statistically-significant improvements in 0-6 hours post-dose WM FEV1 versus PBO+FP/SAL (Day 84: 0.144-0.165 L). Rescue use over Weeks 1-12 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL (Study 1, 0.3 puffs/day [both doses]; Study 2, 0.5 puffs/day [UMEC 125+FP/SAL]). Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL (except for Day 84 Study 2). In Study 1, no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL; however, in Study 2, statistically significant improvements were observed with UMEC 62.5+FP/SAL (Day 28) and UMEC 125+FP/SAL (Days 28 and 84) versus PBO+FP/SAL. The incidence of on-treatment adverse events across all treatment groups was 37-41% in Study 1 and 36-38% in Study 2. Overall, these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD.

Topics: Administration, Inhalation; Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome; Vital Capacity

The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once-daily monotherapy and in combination with the long-acting β2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia's correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1-10: n = 77 subjects received placebo, n = 76 UMEC 500 µg, n = 78 UMEC/VI 125/25 µg, or n = 76 UMEC/VI 500/100 µg; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed-effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was -2.38 ms (90 % prediction interval [PI] -3.82, -0.85) with UMEC 500 µg and -0.50 ms (90 % PI -0.80, -0.18) and -2.01 ms (90 % PI -3.22, -0.72) with UMEC/VI 125/25 µg and 500/100 µg, respectively. For VI, estimates were 5.89 ms (90 % PI 4.89, 6.91) and 7.23 ms (90 % PI 5.88, 8.55) with UMEC/VI 125/25 µg and 500/100 µg, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25 µg (5.39 ms [90 % PI 4.40, 6.47]) and 500/100 µg (5.22 ms [90 % PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses.

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Benzyl Alcohols; Chlorobenzenes; Cross-Over Studies; Drug Combinations; Female; Fluoroquinolones; Healthy Volunteers; Humans; Male; Middle Aged; Moxifloxacin; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tablets; Topoisomerase II Inhibitors; Young Adult

Objective Umeclidinium bromide (UMEC) 62.5 μg is a long-acting muscarinic antagonist (LAMA) that is administered once daily via inhalation for chronic obstructive pulmonary disease (COPD) treatment. The objective of this study was to evaluate the safety and tolerability of long-term treatment with UMEC 125 μg in Japanese patients with COPD. Methods This was a 52 week, multicenter, open-label study to evaluate the safety and tolerability of UMEC 125 μg once daily delivered via a novel dry powder inhaler (nDPI) in Japanese patients with COPD. The primary endpoint was the incidence and severity of all adverse events (AEs) throughout the 52 week treatment period. Clinical trial registration number ClinicalTrials.gov identifier is NCT01702363. Results A total of 153 patients were enrolled in the study. Of these, 131 patients started treatment with UMEC 125 μg, and 111 patients (85%) completed the study. AEs did not differ greatly in incidence over the various time periods (Weeks 0 to 12, 13 to 24, 25 to 36, and 37 to 52 of treatment) and did not increase with continued treatment. The incidence of drug-related AEs associated with the pharmacological effects of LAMAs (including constipation, blurred vision, and thirst) was low. Serious adverse events (SAEs) during the treatment period were reported in 17 patients (13%). SAEs reported in more than one patient were COPD exacerbation and pneumonia (3 patients each, 2%). One SAE of angina pectoris was considered to be drug related. No fatalities were reported during this study. Conclusions No new AEs were identified beyond those attributable to the pharmacological effects of LAMAs. UMEC 125 μg was well tolerated over 52 weeks of treatment in Japanese patients with COPD.

Topics: Administration, Inhalation; Aged; Drug Administration Schedule; Dry Powder Inhalers; Female; Humans; Japan; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Dual therapy with bronchodilators of different pharmacological classes may produce greater lung function improvements than either drug alone. However, the relationship between a patient's response to monotherapy and response to dual bronchodilator therapy is currently unknown. We aimed to investigate whether dual therapy with umeclidinium/vilanterol provides additional benefit over umeclidinium or vilanterol monotherapy in patients with chronic obstructive pulmonary disease (COPD) identified as responsive (increase from baseline in forced expiratory volume in 1s [FEV1] of ≥ 12% and ≥ 200 mL, Day 1) or non-responsive to monotherapy.. In two randomised, double-blind, three-way complete-block, cross-over studies (DB2116132 n = 207; DB2116133 n = 182; intent-to-treat), all patients (moderate-to-very severe COPD) were randomised to 1 of 6 sequences and received once-daily umeclidinium 62.5 mcg, vilanterol 25 mcg, and umeclidinium/vilanterol 62.5/25 mcg (one treatment/14-day period; 10-14-day washout). Key endpoints were 0-6 h weighted mean FEV1 (Day 14) and trough FEV1 (Day 15). Adverse events, vital signs and COPD exacerbations were assessed. Pooled data are presented.. Umeclidinium/vilanterol significantly (p ≤ 0.001, unless stated otherwise) increased 0-6 h weighted mean FEV1 versus umeclidinium in umeclidinium-responders (+114 mL), versus vilanterol in vilanterol-responders (+92 mL) and versus umeclidinium (+70 mL) and vilanterol (+62 mL) in non-responders. Improvements in trough FEV1 occurred with umeclidinium/vilanterol versus umeclidinium in umeclidinium-responders (+77 mL), versus vilanterol in vilanterol-responders (+86 mL), and versus umeclidinium (+42 mL [p = 0.020]) and vilanterol (+58 mL) in non-responders. All treatments were well tolerated.. Once-daily umeclidinium/vilanterol significantly improved lung function in patients with COPD, with quantitatively greater improvements in patients identified as responders to umeclidinium and vilanterol monotherapy than non-responders.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

The fixed-dose, long-acting bronchodilator combination of umeclidinium/vilanterol (UMEC/VI) has not previously been compared with a combination of a long-acting muscarinic antagonist and long-acting β2-agonist in patients with chronic obstructive pulmonary disease (COPD).. This 12-week, randomized, blinded, triple-dummy, parallel-group, non-inferiority study compared once-daily UMEC/VI 62.5/25 mcg with once-daily tiotropium (TIO) 18 mcg + indacaterol (IND) 150 mcg in patients with moderate-to-very-severe COPD. The primary endpoint was the trough forced expiratory volume in 1 s (FEV1) on day 85 (predefined non-inferiority margin -50 mL), and the secondary endpoint was the 0- to 6-h weighted mean (WM) FEV1 on day 84. Other efficacy endpoints [including rescue medication use, the Transition Dyspnea Index (TDI) focal score, and the St. George's Respiratory Questionnaire (SGRQ) score] and safety endpoints [adverse events (AEs), vital signs, and COPD exacerbations] were also assessed.. Trough FEV1 improvements were comparable between treatment groups [least squares (LS) mean changes from baseline to day 85: UMEC/VI 172 mL; TIO + IND 171 mL; treatment difference 1 mL; 95 % confidence interval (CI) -29 to 30 mL], demonstrating non-inferiority between UMEC/VI and TIO + IND. The treatments produced similar improvements in the trough FEV1 at other study visits and the 0- to 6-h WM FEV1 (LS mean changes at day 84: UMEC/VI 235 mL; TIO + IND 258 mL; treatment difference -23 mL; 95 % CI -54 to 8 mL). The results for patient-reported measures (rescue medication use, TDI focal score, and SGRQ score) were comparable; both treatments produced clinically meaningful improvements in TDI and SGRQ scores. The incidence of AEs and COPD exacerbations, and changes in vital signs were similar for the two treatments.. UMEC/VI and TIO + IND, given once daily, provided similar improvements in lung function and patient-reported outcomes over 12 weeks in patients with COPD, with comparable tolerability and safety profiles.. ClinicalTrials.gov study ID NCT02257385; GSK study no. 116961.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Humans; Indans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Tiotropium Bromide; Treatment Outcome

The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD. This study investigated the efficacy and safety of UMEC versus TIO in COPD.. This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study. Patients were randomized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at day 85 (non-inferiority margin -50 mL; per-protocol [PP] population). Other end points included weighted mean FEV1 over 0-24 and 12-24 hours post-dose. Patient-reported outcomes comprised Transition Dyspnea Index score, St George's Respiratory Questionnaire total score, and COPD Assessment Test score. Adverse events were also assessed.. In total, 1,017 patients were randomized to treatment. In the PP population, 489 and 487 patients received UMEC and TIO, respectively. In the PP population, change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29-88; P<0.001). Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 (53 mL, 95% CI: 25-81; P<0.001). Improvements in weighted mean FEV1 over 0-24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12-24 hours post-dose (70 mL; P=0.015). Clinically meaningful improvements in Transition Dyspnea Index and St George's Respiratory Questionnaire were observed with both treatments at all time points. No differences were observed between UMEC and TIO in patient-reported outcomes. Overall incidences of adverse events were similar for UMEC and TIO.. UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85. Safety profiles were similar for both treatments.

Topics: Cholinergic Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide; Treatment Outcome

The combination of the inhaled muscarinic antagonist umeclidinium (UMEC) with the long-acting β2-agonist vilanterol (VI) has been shown to provide significant improvements in lung function compared with UMEC, VI, or placebo (PBO) in patients with chronic obstructive pulmonary disease (COPD). This study was specifically designed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population.. This was a 12-week multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Eligible patients were randomized 1:1 to receive once-daily UMEC/VI 62.5/25 μg (via ELLIPTA(®) dry powder inhaler) or PBO for 12 weeks. The primary endpoint was St George's Respiratory Questionnaire (SGRQ) total score at day 84. Secondary efficacy endpoints included rescue albuterol use (puffs/day) over weeks 1-12 and trough forced expiratory volume in 1 second on day 84. Adverse events were also assessed.. A total of 496 patients were included in the intent-to-treat population in the UMEC/VI (n=248) and PBO (n=248) treatment groups. UMEC/VI 62.5/25 μg provided a significant and clinically meaningful improvement in SGRQ total score at day 84 versus PBO (difference between treatments in SGRQ total score change from baseline: -4.03 [95% confidence interval {CI}: -6.28, -1.79]; P<0.001). UMEC/VI 62.5/25 μg resulted in a statistically significant reduction in rescue albuterol use versus PBO (-0.7 puffs/day [95% CI: -1.1, -0.4]; P<0.001). UMEC/VI 62.5/25 μg provided a significant and clinically meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO (122 mL [95% CI: 71, 172]; P<0.001). The incidence of adverse events was similar between treatments (32% and 30% of patients in the UMEC/VI 62.5/25 μg and PBO groups, respectively).. The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinically important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Europe; Female; Forced Expiratory Volume; Humans; Intention to Treat Analysis; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Recovery of Function; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome; United States

Benefits of triple therapy with a long-acting muscarinic antagonist (LAMA), added to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), have been demonstrated. Limited data assessing the efficacy of the LAMA umeclidinium (UMEC) added to ICS/LABA are available. The aim of this study is to evaluate the efficacy and safety of UMEC added to ICS/LABAs in patients with moderate-to-very-severe COPD. This is a multicentre, randomised, double-blind, parallel-group study. Patients were symptomatic (modified Medical Research Council Dyspnoea Scale score ⩾2), despite receiving ICS/LABA (fluticasone propionate/salmeterol (FP/SAL, branded) 500/50 mcg, budesonide/formoterol (BD/FOR, branded) 200/6 mcg or 400/12 mcg, or other ICS/LABAs) ⩾30 days before the run-in (7±2 days). Patients were randomised 1:1 to once-daily UMEC 62.5 mcg or placebo (PBO), added to twice-daily open-label ICS/LABA for 12 weeks. Primary end point was trough forced expiratory volume in 1 s (FEV1) at Day 85; secondary end point was weighted mean (WM) 0-6 h FEV1 at Day 84; other end points included COPD Assessment Test (CAT) score and Transition Dyspnoea Index (TDI) score. Adverse events (AEs) were investigated. In the UMEC+ICS/LABA and PBO+ICS/LABA groups, 119 and 117 patients were randomised, respectively. Patients received FP/SAL (40%), BD/FOR (43%) and other ICS/LABAs (17%). UMEC+ICS/LABA resulted in significant improvements in trough FEV1 (Day 85) and in WM 0-6 h FEV1 (Day 84) versus PBO+ICS/LABA (difference: 123 and 148 ml, respectively, both P<0.001). Change from baseline for UMEC+ICS/LABA versus PBO+ICS/LABA was significantly different for CAT score at Day 84 (-1.31, P<0.05), but not for TDI score (0.40, P=0.152). AE incidence was similar with UMEC+ICS/LABA (38%) and PBO+ICS/LABA (42%). UMEC+ICS/LABA improved lung function and CAT score in patients with symptomatic COPD versus PBO+ICS/LABA (ClinicalTrials.gov NCT02257372).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quinuclidines

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

Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 μg (delivering 55/22 μg) and UMEC/VI 125/25 μg (delivering 113/22 μg) compared with their monotherapy components (UMEC 62.5 μg, UMEC 125 μg and, VI 25 μg [delivering 55, 113, and 22 μg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2–4 h for UMEC and 1–2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies.. Clinicaltrials.gov NCT01899638 NCT01899638.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; China; Chlorobenzenes; Cross-Over Studies; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Young Adult

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

Umeclidinium (UMEC; long-acting muscarinic antagonist) plus vilanterol (VI; long-acting beta2 agonist [LABA]) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol (FP/SAL) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD). This 12-week, multicentre, double-blind, parallel-group, double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment.. Patients (n = 717) were randomised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg. Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, symptoms, quality of life (QoL) and safety.. Improvements with UMEC/VI versus FP/SAL were 0.080 L (95 % confidence interval: 0.046-0.113; wmFEV1) and 0.090 L (0.055-0.125; trough FEV1) (both p < 0.001). UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL. Both treatments demonstrated a clinically meaningful improvement in symptoms (Transition Dyspnoea Index ≥1 unit) and QoL (St George's Respiratory Questionnaire Total score ≥4 unit decrease from baseline) over 12 weeks. The incidence of adverse events was 28 % (UMEC/VI) and 29 % (FP/SAL); nasopharyngitis and headache were most common.. Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment.. NCT01822899 Registration date: March 28, 2013.

Topics: Administration, Inhalation; Adult; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone-Salmeterol Drug Combination; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) patients with blood eosinophil (EOS) count ≥ 2% benefit from exacerbation reductions with inhaled corticosteroids (ICSs). We conducted post hoc analyses to determine if EOS count ≥ 2% is a marker for greater responsiveness to the bronchodilators umeclidinium (UMEC; long-acting muscarinic antagonist), vilanterol (VI; long-acting β2-agonist) or UMEC/VI combination.. Effects of once-daily UMEC/VI 62.5/25, UMEC 62.5 and VI 25 µg versus placebo on trough forced expiratory volume in one second (FEV1), Transition Dyspnoea Index (TDI), St George's Respiratory Questionnaire (SGRQ) scores and adverse event (AE) incidences in four completed, 6-month studies were assessed by EOS subgroup. Trough FEV1 was also evaluated by ICS use and EOS subgroup. Analyses were performed using a repeated measures model.. At baseline, 2437 of 4647 (52%) patients had EOS count ≥ 2%. Overall, ≈ 50% of patients used ICSs. At day 169, no notable variations were observed in trough FEV1 least squares mean differences between EOS subgroups versus placebo for UMEC/VI, UMEC and VI; results according to ICS use were similar. No differences were reported between EOS subgroups in TDI and SGRQ scores on day 168, or for incidences of AEs, serious AEs and AEs leading to withdrawal.. Response to UMEC/VI, UMEC and VI in terms of trough FEV1, dyspnoea and health-related quality of life was similar for COPD patients with baseline EOS counts ≥ 2 or <2%. EOS count did not appear to predict bronchodilator response in either ICS users or non-users.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Eosinophils; Female; Forced Expiratory Volume; Humans; Leukocyte Count; Male; Middle Aged; Muscarinic Antagonists; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Treatment Outcome

Combination of the inhaled long-acting muscarinic antagonist umeclidinium (UMEC; GSK573719) with the long-acting β2-agonist vilanterol (VI) is an approved maintenance treatment for COPD in the US and EU. We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry.. In this 24-week, Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients were randomized 1:1:1 to UMEC/VI 125/25 μg, UMEC/VI 62.5/25 μg, or placebo. The primary efficacy end point was trough forced expiratory volume in 1 second (FEV1) on day 169; secondary end points were Transition Dyspnea Index (TDI) focal score at week 24 and weighted mean (WM) FEV1 over 0-6 hours postdose on day 1. Additional end points and safety were also assessed.. Both UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo (UMEC/VI 125/25 μg, 0.216 L, [95% confidence interval [CI] 0.175-0.257]; UMEC/VI 62.5/25 μg, 0.151 L, 95% CI 0.110-0.191; both P<0.001). Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo (UMEC/VI 125/25 μg, 0.9, 95% CI 0.3-1.4, P=0.002; UMEC/VI 62.5/25 μg, 0.7, 95% CI 0.1-1.2, P=0.016). On day 1, both UMEC/VI groups improved 0-6-hour WM FEV1 versus placebo (UMEC/VI 125/25 μg, 0.182 L 95% CI 0.161-0.203; UMEC/VI 62.5/25 μg, 0.160 L, 95% CI 0.139-0.181; both P<0.001). Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1-24 (puffs/day, both P<0.001). The incidence of adverse events was similar across groups.. In Asian patients with COPD, once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg resulted in clinically meaningful and statistically significant improvements in lung-function end points versus placebo. Symptomatic and quality of life measures also improved. The safety profile of UMEC/VI was consistent with previous studies.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Asian People; Benzyl Alcohols; Bronchodilator Agents; China; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Recovery of Function; Time Factors; Treatment Outcome; Vital Capacity

Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients. This was a randomised, placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 μg over 12 weeks. The primary end-point was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 85. Secondary end-points were 0-6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index, health outcomes (St George's Respiratory Questionnaire), pharmacokinetics and safety. 246 patients were enrolled; 168 completed the study. On day 85, umeclidinium 62.5 and 125 μg significantly improved least squares mean change from baseline in trough FEV1 (127 and 152 mL, respectively; p<0.001) compared with placebo. On day 84, umeclidinium 62.5 and 125 μg significantly improved least squares mean change from baseline in 0-6-h weighted mean (166 and 191 mL, respectively; p<0.001) and serial FEV1 at each time point (p≤0.003). Significant improvements in least squares mean transitional dyspnoea index focal score for UMEC 125 mg(1.3 units; p,0.05) and change from baseline St George's Respiratory Questionnaire total score for both UMEC doses (-7.9 and -10.87 units, for UMEC 62.5 mg and 125 mg, respectively; both p,0.001) were noted compared with placebo at week 12 [DOSAGE ERROR CORRECTED].The incidence of adverse events was low and similar across treatments. Umeclidinium 62.5 and 125 μg significantly improved lung function, dyspnoea and health status compared with placebo, and were well tolerated in chronic obstructive pulmonary disease patients over 12 weeks.

Topics: Administration, Inhalation; Aged; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Smoking; Treatment Outcome

Combination long-acting bronchodilator therapy may be more effective than long-acting bronchodilator monotherapy in chronic obstructive pulmonary disease (COPD).. To compare the efficacy and safety of once-daily umeclidinium/vilanterol (UMEC/VI) 125/25 mcg with placebo and UMEC or VI monotherapy in COPD.. This was a double-blind, placebo-controlled, parallel-group study. A total of 1493 patients were randomized (3:3:3:2) to 24 weeks of treatment with UMEC/VI 125/25 mcg, UMEC 125 mcg, VI 25 mcg, or placebo once-daily via dry powder inhaler.. Primary efficacy endpoint was trough forced expiratory volume in one second (FEV1) on Day 169 (23-24 h post-dose). Additional lung-function, symptomatic and health-related quality of life endpoints were also assessed. Safety evaluations included: adverse events, vital signs, electrocardiography and clinical laboratory measurements. All active treatments significantly improved trough FEV1 vs placebo (0.124-0.238 L, all p<0.001). Improvements with UMEC/VI 125/25 mcg were significantly greater than for UMEC 125 mcg or VI 25 mcg (0.079 L and 0.114 L; both p≤0.001). Improvements for UMEC/VI 125/25 mcg vs placebo were observed for the transition dyspnea index (1.0 unit; p<0.001), rescue albuterol use at Weeks 1-24 (-1.5 puffs/day) and St. George's Respiratory Questionnaire (-3.60 units, p<0.001). No safety signals were observed.. Once-daily UMEC/VI 125/25 mcg was well tolerated and provided greater improvements in lung function, health status, and dyspnea scores compared with monotherapy components and placebo over 24 weeks. This study supports the use of UMEC/VI 125/25 mcg for the maintenance treatment of COPD.. protocol number: DB2113361; ClinicalTrials.gov identifier: NCT01313637.

Topics: Administration, Inhalation; Adult; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Dry Powder Inhalers; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Treatment Outcome

Umeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD).. This was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 μg administered once daily (QD), and UMEC 15.6 μg and 31.25 μg administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-label treatment arm. The primary efficacy endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary efficacy endpoints included weighted mean FEV1 over 0-24 hours after morning dosing on Day 7, and serial FEV1 at each time point over 24 hours after morning dosing on Day 7. Safety and pharmacokinetics were also examined.. One hundred and sixty-three patients (mean age 59.5 years, 52% female) were randomised. Based on the population dose-response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 μg (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 μg QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 μg and below. UMEC 125 μg QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV1 over 0-12 hours were similar to those observed over 12-24 hours after the second dose of UMEC was administered. UMEC was rapidly absorbed following inhaled dosing and eliminated from plasma. Adverse events, generally mild, were highest with UMEC 125 μg QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5-12%).. UMEC is a potent QD bronchodilator with geometric mean ED50 of 37 μg. A dose ordering over the range of UMEC 15.6-125 μg QD doses was observed, with UMEC 125 μg showing the greatest improvement in trough FEV1.

Topics: Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease (COPD). We aimed to compare the efficacy and safety of umeclidinium (UMEC) plus vilanterol (VI) with tiotropium (TIO) monotherapy, UMEC monotherapy, or VI monotherapy in patients with moderate to very severe COPD.. In two multicentre, randomised, blinded, double-dummy, parallel-group, active-controlled trials, eligible patients (current or former smokers aged 40 years or older with an established clinical history of COPD) were randomly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg, UMEC 62·5 μg plus VI 25 μg, TIO 18 μg, and either VI 25 μg (study 1) or UMEC 125 μg (study 2). All study drugs were used once daily for 24 weeks. TIO was delivered via the HandiHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler. Random assignment (by a validated computer-based system) was done by centre and was not stratified. All patients and physicians were masked to assigned treatment during the studies. The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s (FEV1) on day 169, which was analysed in the intention-to-treat population. Both studies are registered with ClinicalTrials.gov, numbers NCT01316900 (study 1) and NCT01316913 (study 2).. 1141 participants were recruited in study 1, and 1191 in study 2. For study 1, after exclusions, 208, 209, 214, and 212 patients were included in the intention-to-treat analyses for TIO monotherapy, VI monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. For study 2, 215, 222, 215, and 217 patients were included in the intention-to-treat analyses for TIO monotherapy, UMEC monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. In both studies, we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy (study 1, UMEC 125 μg plus VI 25 μg: 0·088 L [95% CI 0·036 to 0·140; p=0·0010]; study 1, UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·141; p=0·0006]; study 2, UMEC 125 μg plus VI 25 μg: 0·074 L [0·025 to 0·123; p=0·0031]; study 2, UMEC 62·5 μg plus VI 25 μg: 0·060 L [0·010 to 0·109; nominal p=0·0182]). Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy (UMEC 125 μg plus VI 25 μg: 0·088 L [0·036 to 0·140; p=0·0010]; UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·142; p=0·0006], but not compared with UMEC 125 μg monotherapy (UMEC 125 μg plus VI 25 μg: 0·037 L [-0·012 to 0·087; p=0·14]; UMEC 62·5 μg plus VI 25 μg: 0·022 L [-0·027 to 0·072; p=0·38]). All treatments produced improvements in dyspnoea and health-related quality of life; we noted no significant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO. The most common on-treatment, severe-intensity adverse event in both studies was acute exacerbation of COPD (1-4 [<1-2%] patients across treatment groups in study 1 and 1-6 [<1-3%] patients in study 2). We recorded five to 15 (2-7%) on-treatment serious adverse events across treatment groups in study 1, and nine to 22 (4-10%) in study 2. We noted no substantial changes from baseline in vital signs, clinical laboratory findings, or electrocardiography findings in any of the treatment groups.. Combination treatment with once-daily UMEC plus VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD. Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD.. GlaxoSmithKline.

Topics: Administration, Inhalation; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

Umeclidinium (UMEC) is an inhaled long-acting muscarinic antagonist approved in the US and EU for the once-daily (QD) treatment of chronic obstructive pulmonary disease (COPD); it is not indicated for the treatment of asthma. To fully characterize the dose-response relationship of UMEC in patients with COPD, a pooled analysis of data from two randomized, placebo-controlled, cross-over, dose-ranging studies was performed, evaluating UMEC at doses of 15.6-1000 mcg QD and 15.6-250 mcg twice daily (BID). The primary endpoint was trough forced expiratory volume in one second (FEV(1)) at the end of each study's treatment period (Day 8/Day 15). A population model-based analysis using total daily UMEC dose was used for the primary analysis comparing QD and BID dosing. A physiological effect (E(max)) model was optimal in defining the relationship between UMEC dose and the primary endpoint, demonstrating a clear monotonic dose response over QD and BID dosing regimens. UMEC doses ≥62.5 mcg QD were differentiated from lower doses and BID dosing did not provide benefit over QD dosing. The potency (ED(50)) estimate was 33 mcg with QD dosing. These data indicate that UMEC 62.5 mcg and 125 mcg QD provide lung function benefits that warrant further investigation for the treatment of COPD.

Topics: Aged; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide

The long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the combination of UMEC with the long-acting β2-agonist (LABA) vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD) in the US and EU. They are not indicated for the treatment of asthma.. In this 52-week, double-blind, placebo-controlled, parallel-group safety study (GSK study DB2113359; NCT01316887), patients were randomized 2:2:1 to UMEC/VI 125/25 mcg, UMEC 125 mcg, or placebo. Study endpoints included adverse events (AEs), clinical chemistry and hematology parameters, vital signs, 12-lead, and 24-hour Holter electrocardiograms. COPD exacerbations and rescue medication use were assessed as safety parameters; lung function was also evaluated.. The incidence of on-treatment AEs, serious AEs (SAEs), and drug-related AEs was similar between treatment groups (AEs: 52-58%; SAEs: 6-7%; drug-related AEs: 12-13%). Headache was the most common AE in each treatment group (8-11%). AEs associated with the LAMA and LABA pharmacologic classes occurred at a low incidence across treatment groups. No clinically meaningful effects on vital signs or laboratory assessments were reported for active treatments versus placebo. The incidences of atrial arrhythmias with UMEC/VI 125/25 mcg were similar to placebo; for UMEC 125 mcg, the incidences of ectopic supraventricular beats, sustained supraventricular tachycardia, and ectopic supraventricular rhythm were ≥2% greater than placebo. With active treatments, COPD exacerbations were fewer (13-15% of patients reporting ≥1 exacerbation) and on average less rescue medication was required (1.6-2.2 puffs/day) versus placebo (24% reporting ≥1 exacerbation, 2.6 puffs/day). Both active treatments improved lung function versus placebo.. UMEC/VI 125/25 mcg and UMEC 125 mcg were well tolerated over 12 months in patients with COPD.

Topics: Aged; Benzyl Alcohols; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD).. Patients with COPD were randomized in two multicentre, double-blind, incomplete block crossover studies. Patients received two of six treatments in sequence (12 weeks each): placebo, umeclidinium (UMEC)/vilanterol (VI) (125/25 mcg or 62.5/25 mcg), VI (25 mcg) or UMEC (62.5 mcg or 125 mcg). Exercise endurance time (EET) and trough forced expiratory volume in 1 second (FEV1) (Week 12) were co-primary endpoints. Safety was monitored throughout.. Both studies showed similar 3-hour post-dose EET improvements from baseline for UMEC/VI (Week 12). Significant EET improvements were observed with both UMEC/VI doses versus placebo at Week 12 in Study 418 (UMEC/VI 125/25 mcg: 65.8 s; p = 0.005; UMEC/VI 62.5/25 mcg: 69.4 s; p = 0.003), but not in Study 417, where a placebo effect was evident. Post hoc integrated data analysis showed significant but smaller EET improvements for both UMEC/VI doses versus placebo at Week 12 (UMEC/VI 125/25 mcg: 47.5 s; p = 0.002; UMEC/VI 62.5/25 mcg: 43.7 s; p = 0.001). Both studies showed trough FEV1 improvements at Week 12 for both UMEC/VI doses. The incidence of adverse events was similar between treatment groups within each study.. UMEC/VI improved lung function and EET.

Topics: Benzyl Alcohols; Chlorobenzenes; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Combinations of inhaled long-acting bronchodilator therapies such as muscarinic antagonists and β2-agonists may be more effective than monotherapy in the treatment of chronic obstructive pulmonary disease (COPD).. This study was a 24-week, Phase III, multicenter, randomized, blinded, double-dummy, parallel-group study of the once-daily, inhaled, fixed-dose combination of the long-acting muscarinic antagonist umeclidinium bromide and the long-acting β2-agonist vilanterol (UMEC/VI 62.5/25 mcg) versus tiotropium (TIO, 18 mcg). The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Day 169. The secondary endpoint was weighted mean FEV1 over 0–6 h post-dose at Day 168. For key endpoints, a step-down closed testing hierarchy was applied to account for multiplicity. Other efficacy and safety endpoints were assessed.. Statistically significant improvements in trough FEV1 at Day 169 (0.112 L, 95% confidence interval [CI]: 0.081, 0.144; p < 0.001) and weighted mean FEV1 over 0–6 h post-dose at Day 168 (0.105 L, 95% CI: 0.071, 0.140; p < 0.001) were observed for UMEC/VI versus TIO. In addition UMEC/VI improved health-related quality of life, and reduced requirement for the use of rescue medication compared with TIO. The incidence of adverse events was similar between treatment groups.. UMEC/VI was associated with statistically significant and clinically meaningful improvements in lung function versus TIO. UMEC/VI was well tolerated. UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe COPD.

Topics: Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The combination of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a selective long-acting β₂ agonist, is in development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacokinetics, safety and tolerability, and pharmacodynamics of once-daily, inhaled UMEC and UMEC/VI when co-administered with oral verapamil, a moderate P-glycoprotein transporter and moderate cytochrome P450 3A4 (CYP3A4) inhibitor frequently used by patients with COPD and cardiovascular comorbidities.. Subjects were randomized to one of two 13-day treatment regimens: UMEC 500 μg or UMEC 500 μg/VI 25 μg. All subjects received a single tablet containing 240 mg verapamil on each of days 9-13.. Repeat doses of UMEC and UMEC/VI in combination with and without verapamil were safe and well tolerated. There was no increase in systemic exposure of UMEC when administered in combination with VI compared to UMEC alone. UMEC maximum concentration was similar with or without verapamil; a moderate increase in UMEC area under the curve (approximately 1.4-fold) was observed with verapamil. Verapamil did not increase systemic exposure to VI following administration of the UMEC/VI combination.. Administration of UMEC and UMEC/VI combination was well tolerated and did not show clinically relevant increases in systemic exposure for either drug. The UMEC/VI combination is unlikely to have a clinically meaningful drug-drug interaction with moderate P-glycoprotein transporter and CYP3A4 inhibitor drugs.

Topics: Administration, Oral; Adolescent; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Benzyl Alcohols; Chlorobenzenes; Drug Combinations; Dry Powder Inhalers; Female; Heart Rate; Humans; Male; Middle Aged; Muscarinic Antagonists; Potassium; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Vasodilator Agents; Verapamil; Young Adult

To examine the efficacy and safety of the once-daily, inhaled, long-acting muscarinic antagonist/β2-agonist combination umeclidinium/vilanterol (UMEC/VI) compared with UMEC and VI monotherapies in patients with chronic obstructive pulmonary disease (COPD).. In this 24-week, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov: NCT01313650) eligible patients were randomised 3:3:3:2 to treatment with UMEC/VI 62.5/25 mcg, UMEC 62.5 mcg, VI 25 mcg or placebo administered once daily via dry powder inhaler (N = 1532; intent-to-treat population). Primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 169 (23-24 h post-dose). Additional lung-function, symptomatic, and health-related quality-of-life endpoints were assessed, including 0-6 h weighted-mean FEV1, rescue salbutamol use, Transition Dyspnoea Index (TDI), Shortness Of Breath With Daily Activity (SOBDA) and St. George's Respiratory Questionnaire (SGRQ) scores. Safety evaluations included adverse events (AEs), vital signs, 12-lead/24-h Holter electrocardiography parameters and clinical laboratory/haematology measurements.. All active treatments produced statistically significant improvements in trough FEV1 compared with placebo on Day 169 (0.072-0.167 L, all p < 0.001); increases with UMEC/VI 62.5/25 mcg were significantly greater than monotherapies (0.052-0.095 L, p ≤ 0.004). Improvements were observed for UMEC/VI 62.5/25 mcg vs placebo for weighted-mean FEV1 on Day 168 (0.242 L, p < 0.001), rescue salbutamol use during Weeks 1-24 (-0.8 puffs/day, p = 0.001), TDI (1.2 units, p < 0.001), SOBDA (-0.17 units, p < 0.001) and SGRQ (-5.51 units, p < 0.001) scores. No clinically-significant changes in vital signs, electrocardiography, or laboratory parameters were observed.. Once-daily UMEC/VI 62.5/25 mcg was well tolerated and provided clinically-significant improvements in lung function and symptoms in patients with COPD.

Topics: Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Severity of Illness Index; Treatment Outcome; Vital Capacity

This study evaluated the dose-response of the new long-acting muscarinic antagonist umeclidinium (GSK573719) in patients with COPD.. This randomized, double-blind, placebo-controlled, parallel-group study evaluated three once-daily doses of umeclidinium (125, 250 and 500 μg) for 28 days in 285 patients with COPD having FEV(1) of 35-70% predicted (mean (SD) age=61.4 (8.41); mean (SD) post-bronchodilator FEV(1)=1.577 (0.450)). The primary endpoint was morning trough FEV(1) at Day 29. Secondary endpoints included 0-6h weighted mean FEV(1) and serial FEV(1) measured over 6h post-dose and at trough. Safety and pharmacokinetics were also assessed.. All doses of umeclidinium significantly increased trough FEV(1) over placebo from 150 to 168 mL (p<0.001), 0-6h weighted mean FEV(1) from 113 to 211 mL (p<0.001), and serial FEV(1) at each point in time over 24h. Reductions in salbutamol use and improvements in FVC were noted for all doses. Umeclidinium was well tolerated with no apparent treatment-related changes in vital signs.. Once-daily umeclidinium provides clinically significant, sustained improvement in lung function and is well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Spirometry

To characterise the safety, tolerability, pharmacodynamics (bronchodilatory effect) and pharmacokinetics of inhaled umeclidinium in patients with chronic obstructive pulmonary disease (COPD). The first investigation was a single dose, randomised, double-blind, placebo-controlled study (clinicaltrials.gov: NCT00515502) in which ipratropium bromide-sensitive patients received umeclidinium (250μg, 500μg, and 1000μg), tiotropium bromide 18μg or placebo. Patients were randomised to receive four out of five possible treatments as an incomplete block four-way cross-over. A subsequent study (clinicaltrials.gov: NCT700732472) was focused on assessment of safety, tolerability and pharmacokinetics of umeclidinium (250μg and 1000μg) administered once-daily for 7 days in a randomised, double-blind, placebo-controlled, parallel-group design. Of the 24 patients randomised for the single dose study, 20 completed; 31 out of 38 patients completed the repeat dose study. Most adverse events were mild-to-moderate and transient. Examination of heart rate, QTc interval, blood pressure and clinical laboratory assessments raised no concern over the safety of umeclidinium. Evidence of pharmacology was demonstrated in first study by statistically significant increases in specific airway conductance (sGaw) for up to 24h for all active treatments compared with placebo. Increases in forced expiratory volume in 1s were also observed. Pharmacokinetic analysis demonstrated that maximum observed plasma umeclidinium concentration (Cmax) was reached rapidly (time to Cmax: ∼5-15min) after single and repeat doses; 1.5-1.9-fold accumulation was observed after repeat-dosing. Single and repeat doses of umeclidinium were well tolerated and produced clinically relevant lung function improvements over 24h in patients with COPD.

Topics: Administration, Inhalation; Aged; Drug Administration Schedule; Female; Heart Rate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Safety

This study evaluated the dose-response and dosing interval of the novel long-acting muscarinic receptor antagonist (LAMA) GSK573719 in patients with COPD.. This randomized, double-blind, placebo-controlled, 3-way cross-over, incomplete block study evaluated 5 once-daily doses of GSK573719 (62.5-1000 μg), 3 twice-daily doses (62.5-250 μg), and open-label tiotropium for 14 days in patients (N = 176) with COPD (FEV(1) of 35-70% predicted). The primary endpoint was morning trough FEV(1) at Day 15. Secondary endpoints included 0-24 h weighted mean FEV(1) and serial FEV(1) values over 28 h. Safety measures and pharmacokinetics were assessed.. All once-daily doses of GSK573719 significantly increased trough FEV(1) at Day 15 with improvements ranging from 95 to 186 mL over placebo (p ≤ 0.006), from 79 to 172 mL with twice-daily dosing (p ≤ 0.03), and 105 mL with tiotropium (p = 0.003). No clear dose ordering was observed. Once-daily doses significantly (p < 0.001) increased 0-24 h weighted mean FEV(1) at Day 14 by 131-143 mL over placebo, comparable to increases with the twice-daily doses (120-142 mL) and tiotropium (127 mL). Significant reductions in rescue albuterol use and improvements in FVC were also observed with once-daily dosing. Plasma C(max) occurred within 5-15 min of dosing after which the drug was rapidly cleared and eliminated. GSK573719 was well tolerated, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters.. Once-daily dosing with GSK573719 in COPD provides clinically significant and sustained improvement in lung function over 24 h with similar efficacy to twice-daily dosing.

Topics: Adult; Aged; Aged, 80 and over; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome; Vital Capacity

Umeclidinium (UMEC; GSK573719) is a new long-acting muscarinic antagonist (LAMA) currently in development in combination with vilanterol (VI), an inhaled, long-acting beta₂ agonist for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to evaluate the safety and tolerability of repeat dosing of UMEC and VI in combination once daily for 28 days in patients with COPD.. This was a multicenter, double-blind, placebo-controlled, parallel group study. Patients aged ≥40 years with post-bronchodilator FEV₁ ≤80% of predicted normal values and FEV₁/FVC ratio ≤0.70, and a smoking history of ≥10 pack-years, were randomized 4:1 to once-daily UMEC/VI (500/25 mcg; n = 42) or placebo (n = 9).. UMEC/VI was non-inferior to placebo in weighted mean pulse rate over 0-6 h at Day 28 (primary endpoint: difference of -0.5 bpm, 95% CI: -5.5 to 4.5). There was no evidence of a difference between UMEC/VI compared with placebo in blood pressure, minimum and maximum pulse rate, or QTcF assessments. Adverse events (AEs) were reported by 11 (26%) patients in the UMEC/VI group and one (11%) patient in the placebo group. No serious AEs were reported. Both UMEC and VI showed rapid absorption (median t(max) ∼6 min for both drugs) with no evidence of accumulation for AUC or C(max) on Day 28 compared with Day 1 for UMEC or VI. There was no correlation between individual steady-state C(max) and pulse rate on Day 28. Change from baseline in trough FEV₁ on Day 29 showed numerically greater improvements with UMEC/VI compared with placebo.. Once-daily dosing with UMEC in combination with VI in patients with moderate-to-very-severe COPD was well tolerated over 28 days.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Aged, 80 and over; Area Under Curve; Benzyl Alcohols; Chlorobenzenes; Delayed-Action Preparations; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Severity of Illness Index; Time Factors; Treatment Outcome

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

Active comparator, new-user, retrospective cohort study using CPRD-Aurum primary care data and linked Hospital Episode Statistics secondary care administrative data. Patients without exacerbations in the previous year were indexed on first/earliest prescription date of once-daily UMEC/VI or twice-daily ICS/LABA as initial maintenance therapy between July 2014-September 2019. Primary outcome: medication adherence at 12 months post-index, defined as proportion of days covered (PDC) ≥80%. PDC represented proportion of time over the treatment duration that the patient was theoretically in possession of the medication. Secondary outcomes: adherence at 6, 18, and 24 months post-index, time-to-triple therapy, time-to-first on-treatment COPD exacerbation, COPD-related and all-cause healthcare resource utilization (HCRU), and direct health-care costs. A propensity score was generated and inverse probability of treatment weighting (IPTW) was used to balance potential confounders. Superiority was defined as >0% difference between treatment groups.. In total, 6815 eligible patients were included (UMEC/VI:1623; ICS/LABA:5192). At 12 months post-index, weighted odds of a patient being adherent were significantly greater with UMEC/VI versus ICS/LABA (odds ratio [95% CI]: 1.71 [1.09, 2.66]; p=0.0185), demonstrating superiority of UMEC/VI. Patients taking UMEC/VI were statistically significantly more adherent than those taking ICS/LABA at 6, 18, and 24 months post-index (p<0.05). Differences in time-to-triple therapy, time-to-moderate COPD exacerbations, HCRU, and direct medical costs were not statistically significant between treatments after IPTW was applied.. At 12 months post-treatment initiation, once-daily UMEC/VI was superior to twice-daily ICS/LABA in medication adherence among patients with COPD without exacerbations in the previous year, newly initiating dual maintenance therapy in England. The finding was consistent at 6, 18, and 24 months.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Chlorobenzenes; Humans; Muscarinic Antagonists; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies

This retrospective cohort study used primary care data from the Clinical Practice Research Datalink Aurum database linked with secondary care administrative data from Hospital Episode Statistics. Patients with a COPD diagnosis at age ≥35 years were included (indexed) following initiation of single-inhaler UMEC/VI or TIO/OLO between July 1, 2015, and September 30, 2019. Outcomes included the number of rescue medication prescriptions at 12-months (primary), and at 6-, 18- and 24-months (secondary), adherence at 6-, 12-, 18- and 24-months post-index, defined as proportion of days covered ≥80% (secondary), and time-to-initiation of triple therapy (exploratory). Inverse probability of treatment weighting (IPTW) was used to balance potential confounding baseline characteristics. Superiority of UMEC/VI versus TIO/OLO for the primary outcome of rescue medication prescriptions was assessed using an intention-to-treat analysis with a p-value < 0.05.. In total, 8603 patients were eligible (UMEC/VI: n = 6536; TIO/OLO: n = 2067). Following IPTW, covariates were well balanced across groups. Patients initiating UMEC/VI had statistically significantly fewer (mean [standard deviation]; p-value) rescue medication prescriptions versus TIO/OLO in both the unweighted (4.84 [4.78] vs 5.68 [5.00]; p < 0.001) and weighted comparison (4.91 [4.81] vs 5.48 [5.02]; p = 0.0032) at 12 months; consistent results were seen at all timepoints. Adherence was numerically higher for TIO/OLO versus UMEC/VI at all timepoints. Time-to-triple therapy was similar between treatment groups.. UMEC/VI was superior to TIO/OLO in reducing rescue medication prescriptions at 12 months after treatment initiation in a primary care cohort in England, potentially suggesting improvements in symptom control with UMEC/VI compared with TIO/OLO.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Drug Prescriptions; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Tiotropium Bromide; Treatment Outcome

This retrospective cohort study used linked primary care electronic health record data (Clinical Practice Research Datalink-Aurum) and secondary care data (Hospital Episode Statistics) to assess outcomes for patients with COPD who had a first prescription for single-inhaler UMEC/VI or IND/GLY (index date) between 1 January 2015 and 30 September 2019 (indexing period). Analyses compared UMEC/VI and IND/GLY on moderate-to-severe, moderate, and severe exacerbations, healthcare resource utilization (HCRU), and direct costs at 6, 12, 18, and 24 months, and time-to-first on-treatment exacerbation up to 24 months post-index date. Following inverse probability of treatment weighting (IPTW), non-inferiority and superiority of UMEC/VI versus IND/GLY were assessed.. In total, 12,031 patients were included, of whom 8753 (72.8%) were prescribed UMEC/VI and 3278 (27.2%) IND/GLY. After IPTW, for moderate-to-severe exacerbations, weighted rate ratios were <1 at 6, 12, and 18 months and equal to 1 at 24 months for UMEC/VI; around the null value for moderate exacerbations and <1 at all timepoints for severe exacerbations. UMEC/VI showed lower HCRU incidence rates than IND/GLY for all-cause Accident and Emergency visits and COPD-related inpatient stays and associated all-cause costs at 6 months post-indexing. Time-to-triple therapy was similar for both treatments.. UMEC/VI demonstrated non-inferiority to IND/GLY in moderate-to-severe exacerbation reduction at 6, 12 and 18 months. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY on reduction of moderate-to-severe exacerbations.

Topics: England; Glycopyrrolate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Retrospective Studies

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

Long-acting beta-agonists (LABA) and long-acting muscarinic antagonists (LAMA) combination therapy improved lung function and health-related quality-of-life and reduced exacerbation rates and dyspnea in symptomatic chronic obstructive pulmonary disease (COPD) patients. We compared the real-world effects of three fixed-dose LABA/LAMA combinations for COPD in Taiwan.. This multicenter, retrospective study evaluated 1-year outcomes after LABA/LAMA combination therapy in patients with symptomatic COPD. Exacerbations and symptoms of COPD, lung functions, and therapy escalation were compared among patients using tiotropium/olodaterol, umeclidinium/vilanterol and indacaterol/glycopyrronium. Propensity score matching (PSM) was applied to balance the baseline characteristics.. Data of 1,617 patients were collected. After PSM, time to first moderate-to-severe COPD exacerbation was comparable among three groups, while the annualized rates of the exacerbation (episodes/patient/year) in patients receiving tiotropium/olodaterol (0.19) or umeclidinium/vilanterol (0.17) were significantly lower than those receiving indacaterol/glycopyrronium (0.38). COPD-related symptoms were stable over the treatment period, and there was no significant difference in the changes of symptom scores including CAT and mMRC among three groups at the end of the study period.. This study presented valuable real-world outcome in terms of exacerbation and treatment response of COPD patients treated with fixed-dose LABA/LAMA regimens in Taiwan. The annualized rates of moderate-to-severe exacerbation in patients receiving tiotropium/olodaterol or umeclidinium/vilanterol were significantly lower than those receiving indacaterol/glycopyrronium, though the time to first moderate-to-severe exacerbation was similar among different fixed-dose LABA/LAMA combinations.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Retrospective Studies; Taiwan; Tiotropium Bromide; Treatment Outcome

Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data.. The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results.. Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (-0.059, 0.168) with total cost savings of £690 (£231, £1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £1336 (£1006, £2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£4/QALY gained) and at the lowest estimate of the St George's Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol.. Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol.

Topics: Administration, Inhalation; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cost-Benefit Analysis; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Salmeterol Xinafoate; Treatment Outcome; United Kingdom

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

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

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Beclomethasone; Benzyl Alcohols; Budesonide, Formoterol Fumarate Drug Combination; Chlorobenzenes; Cohort Studies; Comparative Effectiveness Research; Disease Progression; Drug Combinations; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Glucocorticoids; Glycopyrrolate; Humans; Indans; Male; Muscarinic Antagonists; Pneumonia; Propensity Score; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines

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

Adherence to chronic obstructive pulmonary disease (COPD) maintenance medication is important for managing symptoms and exacerbation risk, and is associated with reduced mortality, hospitalizations, and costs. This study compared on-treatment exacerbations, medical costs, and medication adherence in patients with COPD initiating treatment with umeclidinium/vilanterol (UMEC/VI) or tiotropium (TIO).. Each cohort included 3929 matched patients. Kaplan-Meier rates of on-treatment COPD-related exacerbations were similar between cohorts (hazard ratio at 12 months; overall: 0.93, moderate: 0.92, severe: 1.07; all p > 0.05). UMEC/VI versus TIO initiators had significantly higher adherence (mean PDC: 0.44 vs 0.37; p < 0.001; proportion with PDC ≥ 0.8: 22.0% vs 16.4%; p< 0.001) and significantly lower mean on-treatment COPD-related total medical costs ($867 vs $1095 PPPM; p = 0.028), driven by lower outpatient visit costs.. These findings provide valuable information for physicians considering UMEC/VI or TIO as initial maintenance therapy options for patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Databases, Factual; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Medication Adherence; Middle Aged; Muscarinic Antagonists; Propensity Score; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Time-to-Treatment; Tiotropium Bromide; United States

Smoking may reduce the efficacy of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD), but its impact on bronchodilator efficacy is unclear. This analysis of the EMAX trial explored efficacy and safety of dual- versus mono-bronchodilator therapy in current or former smokers with COPD.. The 24-week EMAX trial evaluated lung function, symptoms, health status, exacerbations, clinically important deterioration, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving ICS. Current and former smoker subgroups were defined by smoking status at screening.. In current and former smokers, umeclidinium/vilanterol provided greater improvements in lung function and symptoms versus umeclidinium and salmeterol, supporting consideration of dual-bronchodilator therapy in symptomatic patients with COPD regardless of their smoking status.. Patients with chronic obstructive pulmonary disease (COPD) often require daily medication to control their COPD. Many patients with COPD are smokers, and smoking is one of the most common causes of COPD. This means that it is important to find out whether COPD medications are effective in both smokers and nonsmokers. We analyzed data from a clinical trial (EMAX) that investigated the use of a combination of two bronchodilators, which are inhaled medications that help to open the airways. We compared umeclidinium/vilanterol, a dual-bronchodilator combination, with a single bronchodilator (either umeclidinium or salmeterol) over 6 months. We found that both current and former smokers who were treated with umeclidinium/vilanterol had larger improvements in lung function than those receiving umeclidinium or salmeterol. Current or former smokers who were treated with umeclidinium/vilanterol used their reliever inhaler less than those treated with umeclidinium or salmeterol. Patients treated with umeclidinium/vilanterol were generally less likely to experience disease worsening compared with umeclidinium or salmeterol if they were former smokers, or compared with salmeterol if they were current smokers. Our findings suggest that umeclidinium/vilanterol may be more effective than a single bronchodilator for daily treatment of patients with COPD who are current or former smokers. Physicians should consider prescribing a combination of two bronchodilators to patients who have symptoms, whether or not they currently smoke, as well as encouraging smoking cessation for all patients.

Topics: Administration, Inhalation; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Smokers; 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

COPD-diagnosed Medicare Advantage enrollees aged ≥65 years were identified from the Optum Research Database (ORD). Eligible patients had ≥1 pharmacy claim for UMEC/VI or FP/SAL in the 6-month period before sample identification, with no evidence of triple therapy (ICS/LAMA/LABA), asthma, or lung cancer. Symptom burden was assessed via cross-sectional surveys using the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Patients were classified into GOLD categories using patient-reported symptoms and claims-based exacerbation history. Treatment groups were balanced on potential confounders using inverse probability of treatment weighting (IPTW). CAT and mMRC scores were analyzed with generalized linear regression models using IPTW propensity scores.. The final analytic sample included 789 respondents (UMEC/VI: N=392; FP/SAL: N=397). Approximately 66% patients were classified as GOLD B when assessing symptoms with CAT and mMRC together, or CAT alone; more patients were classified as GOLD A (~40%) than GOLD B (~36%) using mMRC alone. Proportions of patients in each GOLD group were similar between treatment cohorts. Post-IPTW multivariable modeling showed similar symptom burden between treatment groups.. After controlling for baseline characteristics, symptom burden was similar between patients receiving UMEC/VI or FP/SAL. GOLD classification using mMRC produced more conservative results compared with CAT, potentially underestimating patient symptoms. Many patients receiving FP/SAL were classified as GOLD A or B, despite GOLD recommending non-ICS-containing therapy in these patients. These findings support the need for routine assessment of symptoms in patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cross-Sectional Studies; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Medicare Part C; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome; United States

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 therapies are the therapeutic mainstay in stable chronic obstructive pulmonary disease (COPD). They are represented by long-acting bronchodilators (anticholinergics or beta2-agonists) and by inhaled corticosteroids, currently available as a monotherapy or as combination therapies in one inhaler. Combinations of anticholinergics and beta2 agonists or beta2 agonists and inhaled corticosteroids are widely used per the prescription guidelines. The advantage of them are related with higher adherence and better acceptability by the patients as compared to both components dosed with individual inhalers. Bronchodilator combinations have also been demonstrated to exhibit a superior efficacy due to their synergistic mechanism of action when compared to either monotherapy. Triple therapies with anticholinergic-beta2 agonist-inhaled corticosteroid have been under investigation over the last few years and recently one such product became available in the EU for the treatment of stable COPD. Areas covered: The the FULFIL trial (Lung FUnction and quality of LiFe assessment in COPD with closed trIpLe therapy) investigated the efficacy and safety of fluticasone/vilanterol/umeclidinium once daily therapy in COPD patients. Expert opinion: The results discussed in this paper support the use of this combination in advanced COPD but also in earlier stages in patients with frequent exacerbation. However further and more long-term assessments are required.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cholinergic Antagonists; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines

Retrospective study of patients with COPD enrolled in a US health insurance plan during 2013-2015 and newly initiated on TIO or UMEC/VI. Patients were ≥40 years of age at index (date of therapy initiation) with continuous enrollment for 12 months pre-index and ≥30 days post-index. LAMA users were propensity score matched 1:1 to LAMA/LABA users, with TT initiation rates reported by cohort using pharmacy claims.. 35,357 patients initiating on TIO and 2407 patients initiating on UMEC/VI were identified. After propensity score matching, the rate of TT initiation was significantly higher in new TIO users (n = 1320) than in new UMEC/VI users (n = 1320) (0.92 vs 0.49 per 100 months of exposure, respectively; p < 0.001). Relative to the UMEC/VI cohort, the TIO cohort had an 87% higher risk of TT initiation (hazard ratio: 1.87; 95% confidence interval: 1.4-2.5; p = 0.001).. Patients receiving UMEC/VI progressed to TT more slowly, and were at lower risk of progressing to TT, than patients receiving TIO.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzyl Alcohols; Chlorobenzenes; Delayed-Action Preparations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Tiotropium Bromide; Treatment Outcome

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

Overall, 1637 patients included in the ITT population received UMEC + ICS/LABA (n = 819) or placebo + ICS/LABA (n = 818). Additional bronchodilation with UMEC reduced the risk of a first CID by 45-58% in the ITT population and all subgroups analyzed compared with placebo (all p < 0.001). Improvements were observed in reducing FEV. Symptomatic patients with COPD receiving ICS/LABA experience frequent deteriorations. Additional bronchodilation with UMEC significantly reduced the risk of CID and provided greater short-term stability versus continued ICS/LABA therapy in these patients.. GlaxoSmithKline (study number: 202067). Plain language summary available for this article.

Topics: Aged; Benzyl Alcohols; Chlorobenzenes; Disease Progression; Double-Blind Method; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Respiratory System Agents; Secondary Prevention; Symptom Assessment; 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

The objective of this study was to assess the cost-effectiveness of maintenance treatment with UMEC/VI compared with tiotropium (TIO) 18 μg, open dual LAMA + LABA treatment, or no long-acting bronchodilator treatment in patients with moderate to very severe COPD.. A Markov model was developed to estimate the costs and outcomes associated with UMEC/VI treatment in patients with moderate to very severe COPD (GSK study number: HO-13-13411). Clinical efficacy, costs, utilities, and mortality obtained from the published literature were used as the model inputs. Costs are presented in US dollars based on 2015 prices. The model outputs are total costs, drug costs, other medical costs, number of COPD exacerbations, and quality-adjusted life-years (QALYs). Costs and outcomes were discounted at a 3% annual rate. Incremental cost-effectiveness ratios were calculated. One-way and probabilistic sensitivity analyses were conducted to assess the effects of changing parameters on the uncertainty of the results.. UMEC/VI treatment for moderate to very severe COPD was associated with lower lifetime medical costs ($82,344) compared with TIO ($88,822), open dual LAMA + LABA treatment ($114,442), and no long-acting bronchodilator ($86,751). Fewer exacerbations were predicted to occur with UMEC/VI treatment compared with no long-acting bronchodilator treatment. UMEC/VI provided an 0.11 and 0.25 increase in QALYs compared with TIO and no long-acting bronchodilator treatment, and as such, dominated these cost-effectiveness analyses. Sensitivity analyses confirmed that the results were robust.. The results from this model suggest that UMEC/VI treatment would be dominant compared with TIO and no long-acting bronchodilator treatment, and less costly than open dual LAMA + LABA treatment in patients with moderate to very severe COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Humans; Markov Chains; Models, Economic; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Quinuclidines; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Inhaled bronchodilators - such as long-acting muscarinic receptor antagonists (LAMAs) - are central to the pharmacological management of symptomatic chronic obstructive pulmonary disease. LAMAs are considered to be safe drugs at recommended dosages. In the present issue of the Journal safety of umeclidinium, a recently marketed LAMA, at twice the recommended dosage, has been evaluated with good results in a Japanese, COPD population. However, because muscarinic receptors are expressed not only in the lungs but also at the level of heart, digestive and urinary apparatus, the potential exists for LAMAs to cause adverse events related to stimulation of receptors in these organs. Head-to-head and post-marketing vigilance studies are required to determine the profile risk of these drugs, ultimately, and whether differences exist between currently available LAMAs.

Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Umeclidinium/vilanterol (UMEC/VI) is a novel fixed dose combination of a long-acting muscarinic receptor antagonist (LAMA) and a long-acting beta 2 receptor antagonist (LABA) agent. This analysis evaluated the incremental cost-effectiveness ratio (ICER) of UMEC/VI compared with tiotropium (TIO), from the Spanish National Health System (NHS) perspective.. A previously published linked equations cohort model based on the epidemiological longitudinal study ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) was used. Patients included were COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% and the presence of respiratory symptoms measured with the modified Medical Research Council dyspnea scale (modified Medical Research Council ≥2). Treatment effect, expressed as change in FEV1 from baseline, was estimated from a 24-week head-to-head phase III clinical trial comparing once-daily UMEC/VI with once-daily TIO and was assumed to last 52 weeks following treatment initiation (maximum duration of UMEC/VI clinical trials). Spanish utility values were derived from a published local observational study. Unitary health care costs (€2015) were obtained from local sources. A 3-year time horizon was selected, and 3% discount was applied to effects and costs. Results were expressed as cost/quality-adjusted life years (QALYs). Univariate and probabilistic sensitivity analysis (PSA) was performed.. UMEC/VI produced additional 0.03 QALY and €590 vs TIO, leading to an ICER of €21,475/QALY. According to PSA, the probability of UMEC/VI being cost-effective was 80.3% at a willingness-to-pay of €30,000/QALY.. UMEC/VI could be considered as a cost-effective treatment alternative compared with TIO in symptomatic COPD patients from the Spanish NHS perspective.

Topics: Administration, Inhalation; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cost-Benefit Analysis; Drug Combinations; Female; Forced Expiratory Volume; Humans; Longitudinal Studies; Male; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Quinuclidines; Severity of Illness Index; Spain; Symptom Assessment; Tiotropium Bromide; Treatment Outcome

Treatment with long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) for chronic obstructive pulmonary disease (COPD) is standard, but response varies. We investigated genetic association with treatment response to umeclidinium (UMEC, a LAMA), vilanterol (VI, a LABA), and combination therapy.. Data from 17 clinical trials (N = 6075) in patients with COPD receiving once-daily UMEC/VI (125/25mcg or 62.5/25mcg), UMEC (125 or 62.5mcg), VI (25mcg) or placebo were used. Genetic association with change from baseline in trough forced expiratory volume in 1 s (FEV1) ∼24 h post-dosing was assessed for: (i) 3 β2-adrenoceptor (ADRB2) gene variants; (ii) 298 single-nucleotide polymorphisms (SNPs) with prior evidence of associations; (iii) human leukocyte antigen (HLA) alleles and (iv) genome-wide association study (GWAS) SNPs. Other endpoints were (i) reversibility at screening; and at baseline: (ii) FEV1; (iii) forced vital capacity (FVC), and (iv) FEV1/FVC ratio. Using linear regression, the inverse normal transformed residuals were pooled together, first across treatment group, then across studies for each monotherapy, then combination therapy and finally for every treated patient.. Of 6075 patients, 1849 received UMEC/VI, 1390 received UMEC, 1795 received VI, and 1041 received placebo. None of the ADRB2 variants, HLA alleles or GWAS variants tested were associated with treatment response or baseline endpoints. Four SNPs in FAM13A (rs7671167, rs2869967, rs1964516, rs1903003) were significantly associated with baseline FEV1/FVC ratio (p < 3 × 10(-5)) after adjusting for multiple testing.. No genetic association was found with treatment response to UMEC or VI when administered as monotherapies or in combination.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials as Topic; Drug Combinations; Female; Forced Expiratory Volume; Genome-Wide Association Study; HLA Antigens; Humans; Male; Middle Aged; Muscarinic Antagonists; Pharmacogenetics; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome; Vital Capacity

Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy.. This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George's Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation.. In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001).. This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzyl Alcohols; Chlorobenzenes; Clinical Trials, Phase III as Topic; Disease Progression; Disease-Free Survival; Drug Combinations; Female; Forced Expiratory Volume; Health Status; Humans; Lung; Male; Middle Aged; Multicenter Studies as Topic; Muscarinic Antagonists; Phenethylamines; Propylamines; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Retrospective Studies; Spirometry; Surveys and Questionnaires; Time Factors; Treatment Outcome; Vital Capacity

Handheld inhalers are used to deliver treatment for COPD. Incorrect usage leads to suboptimal disease control. Complex treatment regimens and use of multiple inhalers may reduce patient compliance. The Anoro Ellipta™ dry powder inhaler (DPI) simultaneously delivers umeclidinium bromide (UMEC) and vilanterol (VI) without coformulation being required.. To assess the correct usage and ease of use of the Ellipta™ DPI administering UMEC/VI and to compare patient preference for Ellipta™ with the HandiHaler(®) through exploratory analyses of patient and observer questionnaires in five Phase III studies.. Two Phase III, 3-month double-blind, placebo-controlled studies assessed the correct usage of the Ellipta™ DPI at Day 1 and after 6 weeks, and ease of use of the Ellipta™ DPI using a nonvalidated patient questionnaire after 6 weeks or early withdrawal. In three 6-month, blinded double-dummy, active comparator studies (two Phase IIIa and one Phase IIIb), patients completed a COPD device preference questionnaire between the Ellipta™ DPI and the Handi-Haler(®) at Day 168 (Week 24) or early withdrawal.. In the 3-month placebo-controlled studies, ≥98% of patients used the Ellipta™ DPI correctly and 99% of patients found the inhaler easy/very easy-to-use and the dose counter easy/very easy to read. Across the two Phase IIIa active comparator studies, patients consistently stated a preference for the Ellipta™ DPI over HandiHaler(®) regarding the number of steps to use (59% vs 17%), time taken to use (62% vs 14%), and ease of use (63% vs 15%) regardless of which inhaler contained active drug. Results were consistent in the Phase IIIb active comparator study.. Delivery of UMEC/VI via the Ellipta™ DPI was considered easy-to-use, and patients with COPD demonstrated clear preference for this inhaler compared with HandiHaler(®).

Topics: Administration, Inhalation; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Combinations; Dry Powder Inhalers; Equipment Design; Health Knowledge, Attitudes, Practice; Humans; Lung; Muscarinic Antagonists; Patient Compliance; Patient Education as Topic; Patient Preference; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Surveys and Questionnaires; Time Factors; Treatment Outcome

Long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design.

Topics: Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Comorbidity; Drug Combinations; Evidence-Based Medicine; Humans; Lung; Muscarinic Antagonists; Patient Safety; Patient Selection; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Factors; Time Factors; Tiotropium Bromide; Treatment Outcome

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

Chronic obstructive pulmonary disease (COPD) affects around 64 million people worldwide and is the fourth leading cause of death.(1) It is thought that 3 million people have COPD in the UK, with about 900,000 having been diagnosed and an estimated 2.1 million with disease that remains undiagnosed.(2) In addition, premature mortality from COPD in the UK is almost double the European average and as a result there has been considerable focus on improving outcomes for patients.(3)One of the options for maintenance pharmacological treatment of COPD is a long-acting muscarinic antagonist (LAMA).(4) DTB has previously reviewed three inhaled LAMAs licensed in the UK for use by people with COPD: tiotropium and ▼glycopyrronium (both administered once daily), and ▼aclidinium bromide (administered twice daily).(5-8) ▼Umeclidinium bromide (Incruse) is another once daily LAMA, delivered using the Ellipta inhaler device, and is indicated as maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.(9) Here we review the evidence for its use in the management of COPD.

Topics: Adult; Delayed-Action Preparations; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; United Kingdom

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

Topics: Administration, Inhalation; Benzyl Alcohols; Chlorobenzenes; Drug Approval; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; United States; United States Food and Drug Administration

Umeclidinium/vilanterol (Anoro™ Ellipta™ [USA; Canada; proposed Japan]; Anoro™ [proposed EU]), an inhaled fixed-dose combination of a long-acting muscarinic antagonist and a long-acting β2-adrenergic agonist, is indicated for once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Umeclidinium/vilanterol received its first global approval in this indication in the USA and has subsequently been approved for use in the same indication in Canada, with submissions for regulatory approval in patients with COPD under review elsewhere, including in Europe and Japan. This article summarizes the milestones in the development of umeclidinium/vilanterol leading to its first approval for maintenance treatment of airflow obstruction in patients with COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Chlorobenzenes; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Interactions; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Chronic obstructive pulmonary disease (COPD) mortality is projected to increase by more than 30% in the next 10 years without interventions to cut risks, particularly tobacco smoke exposure. Umeclidinium/vilanterol at 62.5/25 μg is the fixed-dose combination of a long-acting antimuscarinic agent and a long-acting β2-adrenoceptor agonist that administered as dry powder by inhalation was developed for the maintenance treatment of COPD. The combination demonstrated its efficacy in phase III studies where the amelioration of lung function translated into subjective symptomatic improvements. Its long-term safety and tolerability were demonstrated in a 52-week study. Last December, umeclidinium/vilanterol 62.5/25 μg combination was approved, as Anoro™ Ellipta™, by the U.S. Food and Drug Administration (FDA) for maintenance treatment of COPD, being the first FDA-approved once-daily treatment for COPD that contains two long-acting bronchodilators in a single inhaler. It has been filed for approval with the European Medicines Agency.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Animals; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Dry Powder Inhalers; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; United States; United States Food and Drug Administration

A fixed-dose combination of the bronchodilators umeclidinium and vilanterol is in development for the long-term, once-daily treatment of chronic obstructive pulmonary disease (COPD). We characterized the pharmacokinetics of umeclidinium and vilanterol in ≈1,635 patients with COPD, evaluating the impact of patient demographics and baseline characteristics on umeclidinium and vilanterol exposure.. Plasma concentrations of umeclidinium and vilanterol were evaluated in patients enrolled in two phase III, randomized, double-blind, parallel-group, placebo-controlled trials using inhaled umeclidinium/vilanterol combination therapy and inhaled umeclidinium and vilanterol monotherapies as treatments. Population-pharmacokinetic models were developed using non-linear mixed-effects analyses, performed using NONMEM(®) software. A likelihood-based approach was used to characterize the data below limit of quantification. Umeclidinium and vilanterol exposures at clinical doses were simulated based on the population model.. For the umeclidinium and vilanterol population-pharmacokinetic analyses, 1,635 and 1,637 patients provided 8,498 and 8,405 observations, respectively. Umeclidinium and vilanterol pharmacokinetics were best described by a two-compartment model with first-order absorption. For umeclidinium, bodyweight, age, and creatinine clearance (CLCR) were statistically significant covariates for apparent inhaled clearance (CL/F); bodyweight was a statistically significant covariate for volume of distribution of central compartment (V 2/F).The population parameter estimates namely CL/F and V 2/F for umeclidinium were 218 L/h and 1,160 L and 40.9 L/h and 268 L for vilanterol. For vilanterol, bodyweight and age were statistically significant covariates for CL/F. The effect of covariates on umeclidinium and vilanterol systemic exposure was marginal. The population model indicates that a 10 % increase in bodyweight will result in a 2 % increase in CL/F for umeclidinium and vilanterol and 6 % increase in umeclidinium V 2/F. A 10 % increase in age will provide a 7 and 4 % decrease in umeclidinium and vilanterol CL/F, respectively. A 10 % decrease in CLCR will result in a 3 % decrease in umeclidinium CL/F. Umeclidinium and vilanterol population-pharmacokinetic model-based systemic exposure predictions showed no pharmacokinetic interactions between umeclidinium and vilanterol when administered in combination.. There were no apparent pharmacokinetic interactions when umeclidinium and vilanterol were co-administered in patients with COPD. The effects of patient demographics, including age, bodyweight, and CLCR, on umeclidinium or vilanterol systemic exposure were minimal, and therefore no dose adjustments are necessary.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Aged, 80 and over; Area Under Curve; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials, Phase III as Topic; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Models, Biological; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic

Topics: Benzyl Alcohols; Chlorobenzenes; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide