aclidinium-bromide and Pulmonary-Disease--Chronic-Obstructive

Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guideline-based therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Child; Electronic Nicotine Delivery Systems; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Tropanes

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

Currently, combinations of long-acting beta2-agonists and long-acting anticholinergics are considered as the basic therapy for majority of patients with chronic obstructive pulmonary disease (COPD). These combinations have different pharmacological characteristics and delivery devices that provides different clinical effects and new opportunities for personalized treatment of COPD. Aclidinium/formoterol fixed combination differs from other dual bronchodilators by twice-daily dosing regimen, good safety profile and a specific delivery system. Recent information on clinical efficacy and safety of aclidinium/formoterol combination in COPD patients is given in this article.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Combinations; Formoterol Fumarate; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

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

Topics: Administration, Inhalation; Animals; Bronchodilator Agents; Delayed-Action Preparations; Drug Development; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes

Physical activity (PA) is defined as bodily movement produced by skeletal muscles with energy expenditure beyond resting levels. PA is closely related to reduced morbidity and mortality in chronic obstructive pulmonary disease (COPD). Self-report questionnaires are often subject to recall bias, correlating poorly with objectively qualified PA, and do not provide an accurate estimate of free-living energy expenditure. PA may be objectively evaluated by newly developed tri-axial accelerometers by quantifying steps or body movements over a period of time. Low-intensity, home-based pulmonary rehabilitation (PR) using pedometer feedback improves PA. Improvement in physiological factors correlates with increased walking time in stable elderly COPD patients. This review focuses on the effects of PR and pharmacological treatment on PA in COPD patients. We selected 32 studies from our literature search evaluating the effects of PR and 11 studies examining the effects of pharmacological treatment on PA. Findings in both categories were inconsistent. Nineteen studies showed a positive effect with PR whereas 13 showed no effect. Eight studies showed a positive effect, while three revealed no effect from pharmacological intervention. As both interventions increase exercise capacity without a consistent effect on PA, counseling with behavioral changes may be necessary to achieve a significant and lasting increase in PA. Changing PA behavior in COPD patients requires an interdisciplinary approach involving specialists in respiratory medicine, rehabilitation, social, and behavioral sciences. Future research in this area is warranted to advance our knowledge in this area, specifically with regard to the interaction of pharmacological and non-pharmacological interventions.

Topics: Adrenergic beta-2 Receptor Agonists; Behavior; Counseling; Delayed-Action Preparations; Drug Therapy, Combination; Energy Metabolism; Exercise; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Self Efficacy; Terbutaline; Treatment Outcome; Tropanes

To assess the efficacy and safety of combined aclidinium bromide and long-acting beta. We searched the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, World Health Organization (WHO) trials portal, United States Food and Drug Administration (FDA) and manufacturers' websites as well as the reference list of published trials up to 12 October 2018.. Parallel-group randomised controlled trials (RCTs) assessing combined aclidinium bromide and LABAs in people with stable COPD.. We used standard methodological procedures expected by Cochrane for data collection and analysis. The primary outcomes were exacerbations requiring a short course of an oral steroid or antibiotic, or both; quality of life measured by a validated scale and non-fatal serious adverse events (SAEs). Where the outcome or study details were not reported, we contacted the study investigators or pharmaceutical company trial co-ordinators (or both) for missing data.. We identified RCTs comparing aclidinium/formoterol FDC versus aclidinium, formoterol or placebo only. We included seven multicentre trials of four to 52 weeks' duration conducted in outpatient settings. There were 5921 participants, whose mean age ranged from 60.7 to 64.7 years, mostly men with a mean smoking pack-years of 46.4 to 61.3 of which 43.9% to 63.4% were current smokers. They had a moderate-to-severe degree of COPD with a mean postbronchodilator forced expiratory volume in one second (FEV. FDC improved dyspnoea and lung function compared to aclidinium, formoterol or placebo, and this translated into an increase in the number of responders on combination treatment. Quality of life was better with combination compared to formoterol or placebo. There was no evidence of a difference between FDC and monotherapy or placebo for exacerbations, hospital admissions, mortality, non-fatal SAEs or adverse events. Studies reported a lower risk of moderate exacerbations and adverse events with FDC compared to formoterol; however, larger studies would yield a more precise estimate for these outcomes.

Topics: Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Tropanes

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully reversible. While most patients will experience symptoms throughout the day or in the morning upon awakening, many patients do not experience their symptoms as constant but report variability in symptoms during the course of the day or over time. Symptom variability adversely affects patients' health status and increases the risk of COPD exacerbations.. Correct diagnosis and assessment of COPD requires comprehensive clinical and functional evaluation and consideration of individual needs to support the clinical decisions necessary for effective long-term management. Combining bronchodilators from different and complementary pharmacological classes with distinct mechanisms of action can increase the magnitude of bronchodilation as opposed to increasing the dose of a single bronchodilator.. The use of inhaled bronchodilator therapy with LAMA/LABA fixed-dose combinations in patients with stable COPD is supported by current evidence. This treatment approach provides robust effects on lung function and symptom control and may improve patients' adherence to treatment. Administration of the long-acting bronchodilators aclidinium and formoterol as twice daily fixed-dose aclidinium/formoterol 400/12 μg has the potential to control symptoms throughout the 24 h in patients with stable moderate-to-severe COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Forced Expiratory Volume; Formoterol Fumarate; Health Status; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Treatment Outcome; Tropanes; Vital Capacity

As emphasized by international recommendations and largely confirmed by clinical experience, long-acting bronchodilators play a central role in the maintenance treatment of chronic obstructive pulmonary disease (COPD) due to their proven efficacy in reducing airflow obstruction and improving symptoms.. There are some important aspects to define with regard to inhalation therapy for COPD, particularly those concerning the selection criteria and the optimal use of long-acting bronchodilators. First of all, it needs to be determined in which patients and clinical situations monotherapy with one bronchodilator, such as a long-acting muscarinic antagonist (LAMA), should be considered adequate, and in which cases the use of combination therapies, such as the "double bronchodilation" with a LAMA and a long-acting β2-agonist (LABA), should be preferred. Another critical issue concerns the effect of the frequency of daily administration of inhaled agents on the control of symptoms during the 24 h. COPD symptoms are known to exhibit considerable circadian variability with worsening in the early morning, and a significant proportion of patients have disease-related sleep disorders which can adversely affect their quality of life. The worsening of symptoms in the early morning may be due, at least in part, to a reduction in airway caliber caused by an increased "cholinergic tone" at night. As such, the coverage of nighttime and early morning symptoms is a reasonable therapeutic goal, which can be achieved by many patients using LAMAs such as aclidinium bromide twice daily (BID). Therapeutic adherence is known to be a multifactorial phenomenon that is frequently affected by other aspects than dosing frequency, including the technical features and ease of use of the inhalers. To this end, it should be mentioned that certain new-generation inhalers such as Genuair® have been associated in clinical trials with higher patient preference.. In this work, in addition to presenting an overview of the main evidence on the efficacy of COPD treatment with the LAMA aclidinium bromide BID, we suggest some selection criteria for the monotherapy with one long-acting bronchodilator or the combination therapy with LAMA and LABA in COPD patients, with particular reference to specific clinical scenarios.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Clinical Decision-Making; Dose-Response Relationship, Drug; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

Co-administration of a long-acting β2-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice-daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β2-agonist fixed-dose combination that has been studied for this therapeutic indication.

Topics: Administration, Inhalation; Bronchodilator Agents; Clinical Trials as Topic; Drug Synergism; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Tropanes

Bronchodilators are commonly used to manage patients with stable chronic obstructive pulmonary disease (COPD). This meta-analysis assessed the efficacy of aclidinium bromide with respect to clinical events, health-related quality of life and symptom scales, pulmonary function, and safety among patients with stable COPD.. A comprehensive search of MEDLINE, EMBASE, CINAHL and the Cochrane Library databases was undertaken to identify randomized controlled trials (RCTs) that compared aclidinium with placebo, treatment over at least 12 weeks. Trials were measured using either odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI).. Seven studies, containing 7001 patients, were included in this meta-analysis. Compared with placebo, aclidinium bromide reduced the incidence of exacerbation-related hospitalizations (OR 0.64; 95% CI 0.47 to 0.89) and improved quality of life as measured by a lower total George's Respiratory Questionnaire [SGRQ] score (MD -2.34; 95% CI -3.18 to -1.51) and attenuated dyspnea symptom as assessed by changes in the Transitional Dyspnea Index [TDI] (MD 0.76; 95% CI 0.43 to 1.10). Similar changes were observed with regard to trough FEV1 and FVC and peak FEV1 and FVC. No significant differences were observed with regard to all-cause mortality, COPD exacerbations, non-fatal serious adverse events or cardiac adverse events.. Aclidinium reduced the incidence of exacerbation-related hospitalizations and improved quality of life, COPD symptoms and pulmonary function. In addition, aclidinium did not increase the incidence of non-fatal serious adverse events, cardiac adverse events, or COPD exacerbations and was not associated with increased mortality.

Topics: Cause of Death; Disease Progression; Dyspnea; Forced Expiratory Volume; Hospitalization; Humans; Mortality; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome; Tropanes; Vital Capacity

The objective of this study was to estimate the relative efficacy and safety of fixed-dose combination aclidinium/formoterol 400/12 μg twice daily compared to tiotropium 18 μg once daily in adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).. A systematic literature review performed in March 2014, using a predefined search strategy in MEDLINE, EMBASE and Cochrane Library, identified 17 randomized placebo-controlled trials, (tiotropium n = 15; aclidinium/formoterol n = 2). Outcomes of interest were: bronchodilation (peak and trough forced expiratory volume in 1 s (FEV1)), COPD symptoms [Transition Dyspnea Index (TDI) focal score and % of responders (>1 unit improvement)] and Health Related Quality of Life (HRQoL) [St. George's Respiratory Questionnaire (SGRQ) total score and % responders (>4 unit improvement)], % of patients with ≥1 exacerbations, adverse events (AE), serious adverse events (SAE), hospitalization and mortality, all at 24 weeks. In the absence of head-to-head trials between aclidinium/formoterol and tiotropium, a Bayesian indirect treatment comparison (ITC) was used with placebo as common control.. Regarding bronchodilation, aclidinium/formoterol was found to be more efficacious than tiotropium at peak FEV1, with mean difference in change from baseline (DCFB) 143 mL [95% credible interval (CrI): 112, 174] and at trough FEV1 [DCFB 26 mL (95% CrI -2, 55)]. Aclidinium/formoterol is expected to be more efficacious than tiotropium in improving dyspnea symptoms measured by TDI [DCFB 0.54 points (95% CrI 0.09, 0.99); odds ratio (OR) of responders 1.51 (95% CrI 1.11, 2.06)]. SGRQ results are comparable for aclidinium/formoterol versus tiotropium [DCFB -0.52 (95% CrI -2.21, 1.17); OR of responders 1.16 (95% CrI 0.47, 2.87)]. The ITC results suggest similar safety profiles regarding AEs, SAEs and hospitalization.. Based on the ITC, aclidinium/formoterol is expected to be more efficacious than tiotropium in terms of lung function and symptom control while providing comparable HRQoL results and safety profile.. AstraZeneca.

Topics: Bayes Theorem; Bronchodilator Agents; Drug Combinations; Dyspnea; Forced Expiratory Volume; Formoterol Fumarate; Hospitalization; Humans; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Tiotropium Bromide; Tropanes

Aclidinium is a twice-daily long-acting muscarinic receptor antagonist (LAMA) with an interesting pharmacological profile. Recent evidence indicates that this LAMA, in addition to causing a significant improvement in lung function and other important supportive outcomes, such as health related quality of life, dyspnea and nighttime/early morning symptoms in patients suffering from COPD, is also able to significantly reduce the rate of exacerbations of any severity, is extremely effective in controlling the COPD symptoms, is able to reduce lung hyperinflation, and has an excellent cardiovascular safety profile. Consequently, aclidinium should be considered a first-line approach at least for the symptomatic treatment of COPD although there are still few head-to-head studies comparing this LAMA with other bronchodilators. In any case, aclidinium can be taken into account in the treatment of different COPD phenotypes (emphysema, chronic bronchitis, exacerbators and patients with overlap COPD asthma).

Topics: Administration, Inhalation; Bronchial Spasm; Bronchitis, Chronic; Emphysema; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tropanes

The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity.

Topics: Bronchoconstriction; Bronchodilator Agents; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Severity of Illness Index; Time Factors; Treatment Outcome; Tropanes

Drugs that target dynamic hyperinflation such as long-acting β-2 agonists and long-acting antimuscarinic antagonists form a cornerstone of chronic obstructive pulmonary disease (COPD) management. The idea of combining these two medications in a single formulation, which may potentially improve patient compliance, is novel and attractive.. The pharmacologic profiles of aclidinium bromide and formoterol fumarate are discussed. However, studies to define drug interactions and alterations in the pharmacodynamics and pharmacokinetics of the fixed dose combination (FDC) of aclidinium bromide/formoterol fumarate in large populations remain unpublished. Results of Phase II and two Phase III pivotal trials, ACLIFORM/COPD and AUGMENT COPD, evaluating the FDC are discussed.. Initial data for the aclidinium/formoterol inhaler appears to be promising for impacting the lung function. To define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality are important. The introduction of this combination will likely have a significant impact on the prescribing habits of physicians across the world.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tropanes

The recent Global Initiative for Chronic Obstructive Lung Disease (GOLD) chronic obstructive pulmonary disease (COPD) guidelines consider symptoms and exacerbation history in addition to the degree of airflow obstruction for classifying patients. The improvement of symptoms is principally provided by bronchodilators, using β2 agonists and antimuscarinic agents. Aclidinium bromide is a novel long-acting antimuscarinic agent licensed for use in patients with COPD. Novel fixed-dose combinations that are either licensed or in their late phase of development include vilanterol/umeclidinium, indacaterol/glycopyrronium, olodaterol/tiotropium and formoterol/aclidinium. Fixed-dose combinations of aclidinium/formoterol have been evaluated in COPD patients and evidence suggests that this is efficacious, safe, has a quick onset of action and is well tolerated. This review provides a clinico-pharmacological profile of this compound.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Combinations; Formoterol Fumarate; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

This review will be focused on the development of aclidinium bromide/formoterol fumarate (ACLI/FORM) fixed-dose combinations (FDC) that have been granted marketing authorization by the European Commission to be used as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). ACLI/FORM FDC has been studied in 2 pivotal trials involving over 3,400 patients with COPD, in which it was compared with ACLI alone, FORM alone and placebo. The addition of FORM to ACLI resulted in greater bronchodilation than FORM or ACLI alone. ACLI/FORM FDC was also shown to increase the percentage of patients who had an improvement in symptoms and health-related quality of life compared with monotherapies. The frequency of side effects reported with ACLI/FORM FDC was low and their nature did not raise any major safety concern.

Topics: Clinical Trials as Topic; Drug Combinations; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tropanes

Exacerbations of chronic obstructive pulmonary disease (COPD) have important consequences for lung function, health status and mortality. Furthermore, they are associated with high economic costs, predominantly related to hospitalization. They are managed acutely with short-acting bronchodilators, systemic corticosteroids or antibiotics; however, a large proportion of COPD exacerbations are unreported and therefore untreated or self-managed. There is evidence to suggest that these unreported exacerbations also have important consequences for health status; therefore, reducing exacerbation risk is an important goal in the management of COPD. Current guidelines recommend long-acting muscarinic antagonists (LAMAs) as first-line bronchodilator therapy in patients with stable COPD who have a high risk of exacerbation or increased symptoms. To date, three LAMAs, tiotropium bromide, aclidinium bromide and glycopyrronium bromide, have been approved as maintenance bronchodilator treatments for stable COPD. These all provide clinically significant improvements in lung function, reduce symptoms and improve health status compared with placebo in patients with COPD. This paper reviews evidence from randomized, controlled clinical trials demonstrating that tiotropium, aclidinium and glycopyrronium reduce exacerbation risk in patients with COPD. Reductions were seen irrespective of the exacerbation measure used, whether time to first event or annualized exacerbation rate. Furthermore, studies with aclidinium suggest LAMAs can reduce exacerbation risk irrespective of whether exacerbation events are assessed, using an event-based approach or a symptom-based method which includes unreported events. Together these results demonstrate that LAMAs have the potential to provide clinical benefit in the management of exacerbations in patients with stable COPD.

Topics: Clinical Trials as Topic; Delayed-Action Preparations; Glycopyrrolate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Tropanes

Three long-acting muscarinic antagonists (LAMAs) are now available in Europe, providing clinicians and patients with a choice of interventions, which is important in COPD, which is clinically a heterogeneous disease. The first LAMA, tiotropium, has been widely used over the last decade as a once-daily maintenance therapy in stable COPD to improve patients' health-related quality of life and to reduce the risk of exacerbations. Administered via the HandiHaler(®) device, it is safe and well tolerated. Another new once-daily LAMA, glycopyrronium, has also been shown to improve health status and reduce exacerbations, and is well tolerated. The subject of this review is a third LAMA, aclidinium bromide, which was approved as a twice-daily maintenance bronchodilator treatment. In the pivotal Phase III clinical trials, patients receiving aclidinium achieved significantly greater improvements in lung function, reductions in breathlessness, and improvements in health status compared with placebo, for up to 24 weeks. In continuation studies, these improvements were sustained for up to 52 weeks. Pooled data showed exacerbation frequency was significantly reduced with aclidinium versus placebo. Preclinical and pharmacological studies demonstrating low systemic bioavailability and a low propensity to induce cardiac arrhythmias were translated into a favorable tolerability profile in the clinical trial program - the adverse event profile of aclidinium was similar to placebo, with a low incidence of anticholinergic and cardiac adverse events. While additional studies are needed to evaluate its full clinical potential, aclidinium is an important part of this recent expansion of LAMA therapeutic options, providing clinicians and patients with an effective and well-tolerated COPD treatment.

Topics: Bronchodilator Agents; Disease Progression; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Time Factors; Treatment Outcome; Tropanes

The quest for the right combination of bronchodilators with different mechanisms of action such as long-acting muscarinic antagonists and long-acting β-agonists in the management of stable moderate-to-severe chronic obstructive pulmonary disease (COPD) is a topic of intense research activity currently, given the rising morbidity and mortality due to this disease. The fixed-dose combination of aclidinium bromide and formoterol fumarate in a single inhaler seems to offer superior advantages over either drugs given alone or as separate inhalers concurrently. Since the fixed-dose combination needs to be given twice daily, it is likely to achieve control of symptoms most crucial to the quality of life in COPD, namely, the morning hours. This is reflected in significant trough FEV1 (forced expiratory volume in 1 second) improvements after the dose. This paper reviews the various studies related to this combination put in the perspective of its safety and efficacy and potential benefits over other therapeutic options. However, there is a dearth of data on the long-term safety and efficacy in terms of improvement in lung function. This combination could emerge as an excellent option in the management of stable COPD if data on exacerbation rates and patient-reported outcomes become available from longer-term studies. Moreover, we need some more studies to define the ideal phenotype of COPD best suited for the use of this combination.

Topics: Animals; Combined Modality Therapy; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Tropanes

Inhaled bronchodilator therapy is a mainstay of treatment for chronic obstructive pulmonary disease (COPD). Despite the number and types of treatments available, the control of symptoms and exacerbations remains suboptimal, and adherence to, and persistence with, inhaled therapy is generally poor. Results from clinical studies suggest that dual bronchodilator therapy with long-acting muscarinic receptor antagonists (LAMAs) and long-acting β2 adrenergic receptor agonists (LABAs) may provide additional benefit over LAMA or LABA monotherapy without additive effects on safety and tolerability. Several combinations of a LAMA plus a LABA have recently become available in a single inhaler for maintenance therapy for adults with moderate-to-severe COPD, including aclidinium bromide/formoterol fumarate, glycopyrronium/indacaterol and umeclidinium/vilanterol. Here, we review clinical data demonstrating significant improvements in bronchodilation, 24-h symptoms, and health status with aclidinium/formoterol twice daily, and discuss how this treatment can be implemented in clinical practice as part of a patient-focused approach to disease control.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Dyspnea; Formoterol Fumarate; Humans; Lung; Medication Adherence; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Tropanes

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

The safety and efficacy of the second U.S.-approved long-acting inhaled anticholinergic for controlling bronchospasm in patients with chronic obstructive pulmonary disease (COPD) are reviewed.. Aclidinium bromide (Tudorza, Forest Pharmaceuticals) is indicated for long-term maintenance therapy for COPD-associated bronchospasm. It is marketed as a 60-dose metered-dose inhaler to be used twice daily. In Phase II and III clinical trials involving a total of more than 3000 patients, daily use of aclidinium bromide was found to significantly improve selected key indicators of lung function (trough values for forced expiratory volume at one second [FEV1] and other FEV1 outcome measures) compared with placebo use. Other benefits of aclidinium bromide therapy, including a significant reduction in nighttime COPD symptoms, were demonstrated for up to one year. However, aclidinium bromide has not been consistently demonstrated to be more effective than the other currently available long-acting inhaled anticholinergic, tiotropium bromide. Furthermore, the clinical trials indicated no significant difference between aclidinium bromide and tiotropium bromide with regard to rates of systemic adverse effects. For some patients, aclidinium bromide may offer advantages over tiotropium bromide (e.g., a faster time to peak FEV1, lower cost of therapy).. Aclidinium bromide is an inhaled anticholinergic that improves lung function measures in patients with COPD. The most common adverse effects during clinical trials of the drug were headache, nasopharyngitis, and cough, none of which occurred at significantly higher rates than were seen with placebo use.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Tropanes

Chronic obstructive pulmonary disease (COPD) is the sixth-leading cause of death in the US. The Global initiative for Chronic Obstructive Lung Disease (GOLD) guidelines provide evidence-based recommendations for the clinical management of chronic COPD. Long-acting inhaled bronchodilators continue to be the mainstay of current management. Aclidinium bromide (Tudorza™ Pressair™) joins tiotropium as a long-acting inhaled antimuscarinic bronchodilator approved by the US Food and Drug Administration for the maintenance treatment of COPD. Early studies demonstrated aclidinium's significant bronchodilatory effects supporting once-daily dosing; however, two Phase III studies, Aclidinium Clinical Trial Assessing Efficacy and Safety in Moderate to Severe COPD Patients (ACCLAIM/COPD) I and ACCLAIM/COPD II, in which patients were randomized to receive aclidinium 200 μg daily, failed to achieve the minimal clinically important difference in improvement of trough forced expiratory volume in 1 second (FEV1), suggesting the need for higher doses or more frequent dosing. Additional studies - Aclidinium to Treat Airway Obstruction in COPD Patients (ATTAIN) and Aclidinium in Chronic Obstructive Respiratory Disease (ACCORD) I - were undertaken to compare 200 and 400 μg twice-daily dosing. The mean improvements from baseline in trough FEV1 in the 400 μg groups were +129 mL over 24 weeks and +124 mL over 12 weeks in ATTAIN and ACCORD I, respectively. Aclidinium also had beneficial effects on health-related quality of life and other endpoints, such as rescue medication use and rates of exacerbations. Aclidinium bromide inhalation powder is generally well tolerated in patients with COPD, with headache, cough, diarrhea, and rhinosinusitis among the most commonly reported adverse events. Cardiovascular side effects were rarely reported. Patient satisfaction studies found that patients using the aclidinium delivery device had fewer errors affecting drug delivery than those using the tiotropium device and, overall, the aclidinium device was preferred to the tiotropium device. In conclusion, aclidinium bromide is approved for use in the US at a dose of 400 μg twice daily and is a promising alternative to tiotropium.

Topics: Animals; Bronchodilator Agents; Drug Administration Schedule; Forced Expiratory Volume; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Time Factors; Treatment Outcome; Tropanes

Bronchodilators are the mainstay for symptom relief in the management of stable chronic obstructive pulmonary disease (COPD). Aclidinium bromide is a new long-acting muscarinic antagonist (LAMA) that differs from tiotropium by its higher selectivity for M3 muscarinic receptors with a faster onset of action. However, the duration of action of aclidinium is shorter than for tiotropium. It has been approved as maintenance therapy for stable, moderate to severe COPD, but its efficacy and safety in the management of COPD is uncertain compared to other bronchodilators.. To assess the efficacy and safety of aclidinium bromide in stable COPD.. We identified randomised controlled trials (RCT) from the Cochrane Airways Group Specialised Register of trials (CAGR), as well as www.clinicaltrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), US Food and Drug Administration (FDA) website and Almirall Clinical Trials Registry and Results. We contacted Forest Laboratories for any unpublished trials and checked the reference lists of identified articles for additional information. The last search was performed on 7 April 2014 for CAGR and 11 April 2014 for other sources.. Parallel-group RCTs of aclidinium bromide compared with placebo, long-acting beta2-agonists (LABA) or LAMA in adults with stable COPD.. Two review authors independently selected studies, assessed the risk of bias, and extracted data. We sought missing data from the trial authors as well as manufacturers of aclidinium. We used odds ratios (OR) for dichotomous data and mean difference (MD) for continuous data, and reported both with their 95% confidence intervals (CI). We used standard methodological procedures expected by The Cochrane Collaboration. We applied the GRADE approach to summarise results and to assess the overall quality of evidence.. This review included 12 multicentre RCTs randomly assigning 9547 participants with stable COPD. All the studies were industry-sponsored and had similar inclusion criteria with relatively good methodological quality. All but one study included in the meta-analysis were double-blind and scored low risk of bias. The study duration ranged from four weeks to 52 weeks. Participants were more often males, mainly Caucasians, mean age ranging from 61.7 to 65.6 years, and with a smoking history of 10 or more pack years. They had moderate to severe symptoms at randomisation; the mean post-bronchodilator forced expiratory volume in one second (FEV1) was between 46% and 57.6% of the predicted normal value, and the mean St George's Respiratory Questionnaire score (SGRQ) ranged from 45.1 to 50.4 when reported.There was no difference between aclidinium and placebo in all-cause mortality (low quality) and number of patients with exacerbations requiring a short course of oral steroids or antibiotics, or both (moderate quality). Aclidinium improved quality of life by lowering the SGRQ total score with a mean difference of -2.34 (95% CI -3.18 to -1.51; I(2) = 48%, 7 trials, 4442 participants) when compared to placebo. More patients on aclidinium achieved a clinically meaningful improvement of at least four units decrease in SGRQ total score (OR 1.49; 95% CI 1.31 to 1.70; I(2) = 34%; number needed to treat (NNT) = 10, 95% CI 8 to 15, high quality evidence) over 12 to 52 weeks than on placebo. Aclidinium also resulted in a significantly greater improvement in pre-dose FEV1 than placebo with a mean difference of 0.09 L (95% CI 0.08 to 0.10; I(2) = 39%, 9 trials, 4963 participants). No trials assessed functional capacity. Aclidinium reduced the number of patients with exacerbations requiring hospitalisation by 4 to 20 fewer per 1000 over 4 to 52 weeks (OR 0.64; 95% CI 0.46 to 0.88; I(2) = 0%, 10 trials, 5624 people; NNT = 77, 95% CI 51 to 233, high quality evidence) compared to placebo. There was no difference in non-fatal serious adverse events (moderate quality evidence) between aclidinium and placebo.Compared to tiotropium, aclidinium did not demonstrate significant differences for exacerbations requiring oral steroids or antibiotics, or both, exacerbation-related hospitalisations and non-fatal serious adverse events (very low quality evidence). Inadequate data prevented the comparison of aclidinium to formoterol or other LABAs.. Aclidinium is associated with improved quality of life and reduced hospitalisations due to severe exacerbations in patients with moderate to severe stable COPD compared to placebo. Overall, aclidinium did not significantly reduce mortality, serious adverse events or exacerbations requiring oral steroids or antibiotics, or both.Currently, the available data are insufficient and of very low quality in comparisons of the efficacy of aclidinium versus tiotropium. The efficacy of aclidinium versus LABAs cannot be assessed due to inaccurate data. Thus additional trials are recommended to assess the efficacy and safety of aclidinium compared to other LAMAs or LABAs.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Disease Progression; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

Long-acting bronchodilators are central for treatment of COPD. This short review provides an overview of studies evaluating the efficacy of aclidinium bromide, a long-acting anticholinergic bronchodilator, for the treatment of COPD. Twice-daily dosing of aclidinium leads to clinically important improvements in forced expiratory volume in 1 second, health status, use of rescue medication, day-time dyspnoea and exercise tolerance. The available studies also suggest an effect on night-time dyspnoea and exacerbation rate in patients with COPD. Aclidinium seems to have potential for a significant role in the future management of COPD.

Topics: Administration, Inhalation; Bronchodilator Agents; Delayed-Action Preparations; Dyspnea; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Radiography; Treatment Outcome; Tropanes

Inhaled bronchodilators remain a cornerstone of treatment for chronic obstructive pulmonary disease (COPD); current guidelines recommend initiating inhaled bronchodilators as either monotherapy or combination therapy depending on disease severity and exacerbation risk to improve air flow and reduce breathlessness. Aclidinium bromide is a twice-daily, long-acting muscarinic antagonist recently approved in the United States and Europe and carries significant promise as an alternative long-acting inhaled antimuscarinic agent for the treatment of moderate-to-severe COPD.. This review describes the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of aclidinium bromide.. Clinical trials have demonstrated improvement in forced expiratory volume in 1 second, nighttime symptom control, disease-related quality of life, and delay in time to first COPD exacerbation with aclidinium use compared with placebo. Commonly reported adverse effects include headache, nasopharyngitis, and cough. One trial reported narrow-angle glaucoma; however, no other serious adverse events have been reported to date.. Overall, aclidinium bromide has been found to be safe and effective for the treatment of moderate-to-severe COPD. Further clinical trials comparing aclidinium bromide to standard therapies are needed to fully elucidate its role in the treatment of COPD.

Topics: Adult; Clinical Trials as Topic; Contraindications; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes

The inhaled, long-acting muscarinic antagonist, aclidinium bromide, was indicated in July 2012 in Europe and the USA for the maintenance of bronchodilator treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. Although initially investigated as a once-daily agent, a lower than expected improvement in trough forced expiratory volume over 1 s prompted re-evaluation as a twice-daily (b.i.d.) regimen. The dose approved for use in Europe, 400 μg b.i.d., achieved statistically significant improvements in lung function, reductions in breathlessness, and improved health-related quality of life (HRQoL) for up to 24 weeks of treatment in the pivotal phase 3 trials (AClidinium in Chronic Obstructive Respiratory Disease I [ACCORD COPD I] [12 weeks] and Aclidinium To Treat Airway obstruction In COPD patieNts [ATTAIN] [24 weeks]). These improvements were sustained during maintenance therapy of up to 52 weeks. Pooled data from the ATTAIN and ACCORD studies (both included a placebo arm) showed that exacerbation frequency was significantly reduced, although neither study was prospectively designed to evaluate this endpoint. Pharmacological and preclinical studies demonstrated the low systemic bioavailability of aclidinium and the low propensity to induce cardiac arrhythmias. The good tolerability of aclidinium was confirmed in the phase 3 program up to 52 weeks of treatment. The adverse event (AE) profile of the approved dose, 400 μg b.i.d., was similar to that of placebo, with a low incidence of anticholinergic and cardiac AEs. Aclidinium is delivered via the Genuair(®) multidose dry powder inhaler (Almirall Sofotec GmBH, Bad Homburg, Germany). The device is simple to use with multiple feedback mechanisms ensuring consistent dose delivery. In summary, aclidinium 400 μg b.i.d. is effective for the treatment of patients with COPD, offering improvements in lung function, breathlessness, and HRQoL, with a good safety profile and a low incidence of anticholinergic and cardiac AEs.

Topics: Bronchodilator Agents; Dose-Response Relationship, Drug; Dry Powder Inhalers; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

Although there are some challenges with current therapies, the growing evidence that tiotropium bromide is important in the maintenance treatment of chronic obstructive pulmonary disease (COPD) has led to enthusiastic investigation in search of novel muscarinic antagonists which share some of the beneficial characteristics of tiotropium and perhaps improve upon less desirable ones.. Aclidinium bromide is a new muscarinic antagonist that has been developed to relieve symptoms in patients with COPD. Preclinical data showed that it has an intriguing pharmacodynamic and pharmacokinetic profile. Aclidinium bromide was initially assessed as a once-daily bronchodilator. Subsequently, it has been evaluated as a twice-daily agent to increase the size of the clinical effect. Pivotal Phase III trials have documented that aclidinium bromide 400 μg twice-daily shows clinically meaningful effects in lung function and other important supportive outcomes, such as health-related quality of life, dyspnea and night-time/early morning symptoms, and is safe.. Aclidinium bromide can to be used as an alternative to tiotropium or a long-acting β₂-agonist. It is likely that the device used to deliver aclidinium, Genuair inhaler, a novel, multidose and a breath-actuated dry powder inhaler (DPI), will be important for the possible success of this drug. However, additional Phase III trials to assess advantages over tiotropium bromide and long-acting β₂-agonists are required to allow the place of aclidinium bromide to be fully elucidated.

Topics: Administration, Inhalation; Animals; Bronchodilator Agents; Clinical Trials, Phase III as Topic; Dry Powder Inhalers; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

Aclidinium bromide is a new long-acting muscarinic antagonist (LAMA) indicated for maintenance bronchodilator treatment of chronic obstructive pulmonary disease (COPD). The efficacy of aclidinium was compared with tiotropium and glycopyrronium, using a network meta-analysis (NMA) of randomized controlled trials (RCTs) in moderate-to-severe COPD patients.. A systematic review was performed to identify RCTs evaluating aclidinium 400 μg twice daily (BID), glycopyrronium 50 μg once daily (OD), tiotropium 18 μg OD, or tiotropium 5 μg OD in adults with moderate-to-severe COPD. The outcomes of interest were: trough forced expiratory volume in 1 second (FEV1); St George's Respiratory Questionnaire (SGRQ) total score and proportion of patients achieving ≥4 unit change; Transition Dyspnea Index (TDI) focal score and proportion of patients achieving ≥1 point change. The results were synthesized by means of a Bayesian NMA.. Twenty-one studies (22,542 patients) were included: aclidinium 400 μg BID (three studies); tiotropium 5 μg OD (three studies); tiotropium 18 μg OD (13 studies); and glycopyrronium 50 μg OD (two studies). Regarding trough FEV1 at 24 weeks, aclidinium demonstrated comparable efficacy to tiotropium 5 μg (difference in change from baseline [CFB]), (0.02 L [95% credible interval CrI -0.05, 0.09]); tiotropium 18 μg (0.02 L [95% CrI -0.05, 0.08]); and glycopyrronium (0.00 L [95% CrI -0.07, 0.07]). Aclidinium resulted in higher improvement in SGRQ score at 24 weeks, compared to tiotropium 5 μg (difference in CFB, -2.44 [95% CrI -4.82, -0.05]); and comparable results to tiotropium 18 μg (-1.80 [95% CrI -4.52, 0.14]) and glycopyrronium (-1.52 [95% CrI -4.08, 1.03]). Improvements in TDI score were comparable for all treatments.. Maintenance treatment with aclidinium 400 μg BID is expected to produce similar improvements in lung function, health-related quality of life, and dyspnea compared to tiotropium 5 μg OD; tiotropium 18 μg OD; and glycopyrronium 50 μg OD.

Topics: Bayes Theorem; Bronchodilator Agents; Forced Expiratory Volume; Glycopyrrolate; Humans; Lung; Muscarinic Antagonists; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Tropanes

This article reviews the Genuair(®) inhaler, a novel, multidose, breath-actuated dry powder inhaler. The inhaler design includes visual and acoustic feedback to reassure patients that they have taken their medication correctly, a dose indicator and a lock-out mechanism to prevent the use of an empty inhaler. The inhaler has medium airflow resistance and uses an optimised dispersion system to ensure effective deagglomeration of the inhalation powder. In vitro studies have demonstrated that the inhaler delivers a reproducible aerodynamic aerosol quality and is reliable under various thermal and mechanical stress conditions. Further studies in vitro have demonstrated that the total emitted dose and fine particle dose are both consistent over a range of inhalation flows from 45 to 95 l/min, as well as being independent of inhalation volume (2 l vs. 4 l) and storage conditions. In healthy subjects, delivery of aclidinium bromide 200 μg via the inhaler achieved high lung deposition (approximately 30% of the metered dose). A further study has shown that patients with moderate or severe chronic obstructive pulmonary disease can generate sufficient inspiratory airflow through the inhaler to reliably inhale the full dose and reset the inhaler. The inhaler has been used to deliver aclidinium in many clinical trials and the available data indicate that it has high acceptability amongst patients.

Topics: Administration, Inhalation; Aerosols; Asthma; Clinical Trials as Topic; Dry Powder Inhalers; Equipment Design; Humans; Metered Dose Inhalers; Muscarinic Antagonists; Patient Education as Topic; Patient Satisfaction; Pulmonary Disease, Chronic Obstructive; Tropanes

Long-acting muscarinic antagonists (LAMAs) play a central role in the management of chronic obstructive pulmonary disease (COPD). Previously, only one LAMA (tiotropium) was available for the treatment of COPD, necessitating the development of other therapeutic options due to the heterogeneity of COPD and patient responses to treatment. This article reviews the COPD management potential of aclidinium bromide, a LAMA administered twice daily (BID) by a multidose dry powder inhaler that is indicated for maintenance treatment of COPD. Aclidinium possesses kinetic selectivity for the M(3) versus M(2) receptor and is rapidly hydrolyzed in plasma to two major inactive metabolites, resulting in a low and transient systemic exposure and minimizing the potential for systemic side effects. A pharmacokinetic study with multiple doses of twice-daily aclidinium demonstrated the short half-life of aclidinium in plasma, suggesting that a steady state may be reached as early as the second day postdose. In a phase II study, twice-daily aclidinium 400 µg provided 24-hour bronchodilation, with significant improvements versus tiotropium during the second half of the day. In two phase III studies (ACCORD I and ATTAIN), both aclidinium 200 µg and 400 µg BID provided statistically significant improvements in trough forced expiratory volume in 1 second (FEV(1)) and other related lung function measurements. Improvements in peak FEV(1) on day 1 were comparable to those at study end, demonstrating that aclidinium provides maximal bronchodilation after the first dose that is maintained over time. Health status was significantly improved and dyspnea, nighttime and morning symptoms of COPD were likewise significantly reduced with aclidinium. Numerically greater improvements in efficacy were observed with the 400 µg dose compared with the lower dose, with similar safety profiles between the two doses and a low incidence of anticholinergic side effects. The approved therapeutic dose of aclidinium 400 µg BID is thus an effective new treatment option for patients with COPD.

Topics: Animals; Bronchodilator Agents; Delayed-Action Preparations; Dry Powder Inhalers; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

Topics: Administration, Inhalation; Animals; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tropanes

Chronic obstructive pulmonary disease is characterized by poorly reversible airflow obstruction. Long-acting bronchodilators improve lung function and relieve dyspnea. Aclidinium bromide is a novel long-acting antimuscarinic bronchodilator; Phase III clinical trials have demonstrated that administration of this drug twice per day improves lung function, dyspnea and health-related quality of life. Aclidinium bromide is delivered using the Genuair(®) device, which is an easy to use multidose dry powder inhaler. Aclidinium bromide is rapidly metabolized in the plasma, so there is low systemic exposure that minimizes the anticholinergic side effects. This new long-acting bronchodilator provides effective bronchodilation with minimal side effects.

Topics: Acetylcholine; Bronchodilator Agents; Clinical Trials as Topic; Dry Powder Inhalers; Exercise Tolerance; Humans; Ipratropium; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Signal Transduction; Tiotropium Bromide; Tropanes

Inhaled aclidinium bromide has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration for the maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). Aclidinium bromide is a competitive muscarinic receptor antagonist with kinetic selectivity for the muscarinic M(3) receptor and with a long duration of action. It is rapidly hydrolyzed in human plasma, and its metabolites have no activity on muscarinic receptors. Initial phase I and II studies in patients with COPD indicated that aclidinium bromide 200 μg o.d. had a bronchodilator activity up to 24 hours. However, in subsequent phase III studies, the bronchodilator effect at 24 hours was found to be suboptimal. Phase III trials using 200 and 400 μg b.i.d. have subsequently reported both clinical significant bronchodilator activities and improved patient-reported outcomes such as quality of life and dyspnea. Aclidinium bromide was also found to be safe and the anticholinergic side effects were reported to be low.

Topics: Clinical Trials as Topic; Humans; Pulmonary Disease, Chronic Obstructive; Tropanes

Aclidinium is a potent and selective muscarinic antagonist, which interacts rapidly with muscarinic receptors and shows subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)); its association rate for the M(3) receptor is similar to that of ipratropium and 2.6 times faster than that of tiotropium. Aclidinium dissociates slightly faster from M(2) and M(3) receptors than tiotropium but much more slowly than ipratropium. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Aclidinium undergoes rapid hydrolysis in the plasma into two major compounds, the alcohol (LAS34823) and the carboxylic acid (LAS34850) metabolites, resulting in low and transient systemic exposure to the active drug. The two major metabolites show no significant affinity for human muscarinic receptors. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Clinical trials have provided evidence of sustained bronchodilation similar to that observed with tiotropium. Trial results have confirmed the positive safety profile of aclidinium, particularly in terms of a very low propensity to cause anticholinergic adverse events. Aclidinium is now moving to phase III clinical development for chronic obstructive pulmonary disease (COPD).

Topics: Clinical Trials as Topic; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Tropanes

Bronchodilators provide the mainstay of pharmacologic therapy for chronic obstructive pulmonary disease (COPD), and anticholinergic bronchodilators, in particular, appear to be the most effective. There are currently two anticholinergic agents available in the US for the treatment of COPD (ipratropium bromide and tiotropium bromide), but several others are in various stages of development. Aclidinium bromide, a novel, long-acting, anticholinergic bronchodilator, is currently in Phase III trials for the management of COPD. Available evidence suggests that aclidinium is a safe and well tolerated drug with a relatively rapid onset and a sufficient duration of action to provide once-daily dosing. This article will provide a pharmacologic profile of aclidinium bromide and review the preclinical and clinical studies evaluating its safety and efficacy in the treatment of COPD.

Topics: Animals; Bronchodilator Agents; Evidence-Based Medicine; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Time Factors; Treatment Outcome; Tropanes

Aclidinium bromide is a novel, inhaled, long-acting antimuscarinic agent being developed by Almirall Prodesfarma SA and Forest Laboratories Inc as a once-daily treatment for COPD. In preclinical studies, aclidinium bromide demonstrated a comparable profile to tiotropium bromide, with a slightly quicker onset of action but shorter duration of action. Clinical trials have demonstrated an unquestionably interesting pharmacological profile characterized by a faster rate of onset of the smooth muscle relaxing activity than tiotropium bromide and a rapid plasma hydrolysis in human plasma to inactive metabolites that may account for its favorable cardiovascular safety profile. However, the disappointing efficacy results of the recent phase III trials have cast doubt on the real advantage of introducing this drug on the market. Discussions with the FDA concluded that more trials are needed to assess selected dosing regimens, including higher and/or more frequent doses. At the time of publication, further phase III trials with aclidinium bromide were ongoing, and the developing companies were also extending development to combinations of aclidinium bromide with formoterol or an undisclosed inhaled corticosteroid.

Topics: Animals; Bronchodilator Agents; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Tropanes

Long-acting muscarinic antagonists (LAMAs), long-acting β. A total of 3589 patients were included (LABA, n = 227; ICS, n = 290; LABA + ICS, n = 2058; no maintenance, n = 1130). Aclidinium did not increase the risk of MACE or all-cause mortality versus placebo, regardless of baseline maintenance treatment. Reductions in moderate-to-severe exacerbation rates were observed with aclidinium versus placebo in all subgroups [LABA 43% (P = 0.046); ICS 25% (P = 0.202); LABA + ICS 22% (P = 0.003); no maintenance 18% (P = 0.130)]. Aclidinium improved morning trough FEV. In patients with moderate-to-severe COPD and CV risk factors, the addition of aclidinium to maintenance therapy with LABA or LABA + ICS provided further benefit.. ClinicalTrials.gov identifier NCT01966107.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes

Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users.. ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year.. This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity.. ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://clinicaltrials.gov/ct2/show/NCT01966107 .

Topics: Adrenergic beta-Antagonists; Aged; Canada; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Time Factors; Treatment Outcome; Tropanes; United States; Vital Capacity

COPD is associated with nighttime respiratory symptoms, poor sleep quality, and increased risk of nocturnal death. Overnight deterioration of inspiratory capacity (IC) and FEV. What is the effect of evening dosing of dual, long-acting bronchodilation on detailed nocturnal respiratory mechanics and inspiratory neural drive (IND)?. A double-blind, randomized, placebo-controlled crossover study assessed the effects of evening long-acting bronchodilation (aclidinium bromide/formoterol fumarate dihydrate: 400/12 μg) or placebo on morning trough IC (12 h after the dose; primary outcome) and serial overnight measurements of spirometry, dynamic respiratory mechanics, and IND (secondary outcomes). Twenty participants with COPD (moderate/severe airway obstruction and lung hyperinflation) underwent serial measurements of IC, spirometry, breathing pattern, esophageal and transdiaphragmatic pressures, and diaphragm electromyography (diaphragmatic electromyography as a percentage of maximum; IND) at 6 time points from 0 to 12 h after the dose and compared with sleeping IND.. Compared with placebo, evening bronchodilation was not associated with increased morning trough IC 12 h after the dose (P = .48); however, nadir IC (lowest IC, independent of time), peak IC, area under the curve for 12 h after the dose, and IC for 10 h after the dose were improved (P < .05). During placebo, total airways resistance, lung hyperinflation, IND, and tidal esophageal and transdiaphragmatic pressure swings all increased significantly overnight compared with baseline evening values; however, each of these parameters improved with bronchodilator treatment (P < .05) with no change in ventilation or breathing pattern.. Respiratory mechanics significantly deteriorated at night during placebo. Although the morning trough IC was unchanged, evening bronchodilator treatment was associated consistently with sustained overnight improvements in dynamic respiratory mechanics and inspiratory neural drive compared with placebo CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02429765.

Topics: Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Inspiratory Capacity; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Mechanics; Sleep; Spirometry; Tropanes

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Cough; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Placebos; Pulmonary Disease, Chronic Obstructive; Tropanes

There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD).. To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors.. Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017.. Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years.. The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization.. Among 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]).. Among patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year.. ClinicalTrials.gov Identifier: NCT01966107.

Topics: Administration, Inhalation; Aged; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Patient Acuity; Pulmonary Disease, Chronic Obstructive; Risk Factors; Tropanes

Chronic obstructive pulmonary disease (COPD) is mainly treated pharmaceutically with bronchodilators. The purpose of this study was to evaluate the clinical benefits of two-times-per-day aclidinium bromide (Acli-BID) compared with once-a-day tiotropium bromide hydrate (Tio-QD) in patients with COPD.. This study was a multicentre, open-label, randomised study.. Fourcentres in Kagawa prefecture, Japan.. Patients who were diagnosed to have COPD Grade 2-3 according to the Global Initiative for Chronic Obstructive Lung Disease 2015 criteria were enrolled.. Patients were randomly assigned to receive Acli-BID or Tio-QD at a 1:1 ratio, and followed for 8 weeks. Acli-BID was administered in the morning and night, and Tio-QD was administered in the night.. Primary outcome was forced expiratory volume in one second area under the curve (FEV. 44 patients were included in this study. FEV. Acli-BID as with Tio-QD could be one of the therapeutic options for patients with COPD to improve pulmonary function. Also, our results suggest that intervention with bronchodilators enhanced physical activity in patients with COPD.. UMIN 000020020.

Topics: Aged; Bronchodilator Agents; Exercise; Female; Forced Expiratory Volume; Humans; Japan; Linear Models; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Tropanes

Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 μg efficacy and safety was demonstrated in two 6-month Phase III studies (AUGMENT and ACLIFORM) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This Phase III, double-blind, placebo-controlled, 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 μg (NCT01572792).. Patients were randomised in AUGMENT (1:1:1:1:1) to twice-daily AB/FF 400/12 μg, AB/FF 400/6 μg, AB 400 μg, FF 12 μg or placebo. Patients completing AUGMENT were invited to continue the same treatment in the extension. Adverse events (AEs), major adverse cardiovascular events (MACE), laboratory tests, electrocardiograms and vital signs were recorded. Efficacy was assessed.. Of 1322 patients completing AUGMENT, 921 enrolled and 780 completed the extension. AE incidence was low and comparable across treatment groups; most common were nasopharyngitis (range 4.8%-9.3%), urinary tract infection (range 4.1%-8.8%) and upper respiratory tract infection (range 2.7%-5.5%). Serious AEs (SAEs) and MACE were low (ranges 6.8%-7.7% and 0.5%-1.5%, respectively). Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo. Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies. AB/FF combinations increased the time to first exacerbation by approximately 30% versus placebo (p < 0.05).. AB/FF 400/12 μg was well tolerated over 52 weeks with low incidences of AEs, SAEs and MACE that were comparable across treatment groups. Improvements in bronchodilation, symptoms and health status were maintained across 52 weeks.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Health Status; Humans; Male; Middle Aged; Muscarinic Antagonists; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Tropanes

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Germany; Humans; Male; Middle Aged; Muscarinic Antagonists; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Sleep; Sleep Wake Disorders; Smoking; Tropanes

A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study.. Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed.. In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV. In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity.

Topics: Activities of Daily Living; Aged; Bronchodilator Agents; Circadian Rhythm; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

Bronchodilator therapy is the backbone of the management of chronic obstructive pulmonary disease. In some patients, inhaled corticosteroids can be prescribed in combination with bronchodilators. Through a subgroup analysis of pooled data from two large phase III clinical trials of bronchodilator therapy according to concomitant inhaled corticosteroid use (user vs. non-user), we sought to evaluate the clinical benefit of adding inhaled corticosteroids to dual bronchodilator therapy in chronic obstructive pulmonary disease. The primary focus of this analysis of pooled data from the phase III ACLIFORM and AUGMENT studies was to evaluate the efficacy of aclidinium/formoterol on lung function stratified by inhaled corticosteroid use. We found that lung-function end points were significantly improved regardless of concomitant inhaled corticosteroid use among patients treated with the dual bronchodilator aclidinium/formoterol 400/12 µg twice daily compared with placebo and both monotherapies. Together with the previously reported observations that aclidinium/formoterol 400/12 µg reduces exacerbations vs. placebo in inhaled corticosteroid users and improves dyspnoea compared to monotherapy in inhaled corticosteroid non-users, these data suggest that both groups achieve lung function improvements, which translates to different clinical benefits depending on whether or not a patient is receiving concomitant inhaled corticosteroids.CHRONIC LUNG DISEASE: 'TRIPLE' THERAPY COULD PROVE BENEFICIAL: A dual bronchodilator therapy taken together with corticosteroid inhalers may benefit patients with severe chronic lung disease. Bronchodilator drugs relax the lungs and widen airways in patients with chronic obstructive pulmonary disease (COPD). While recent studies have shown that a dual bronchodilator therapy containing aclidinium and formoterol significantly improves lung function in COPD, little is known about combining the dual therapy with inhaled corticosteroids (ICSs). Anthony D'Urzo at the University of Toronto, Canada, and co-workers analysed data from 3394 patients with COPD undergoing dual therapy trials. Of these, 1180 were already taking ICSs. The team compared symptoms in the ICS group with those not taking ICSs. The dual therapy improved lung function across both groups regardless of ICS use, though patients gained different clinical benefits depending on ICS use and disease severity.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Beclomethasone; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Dyspnea; Female; Fluticasone; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tropanes

Long-acting muscarinic antagonists confer improvements in spirometry when used in addition to inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) in COPD. The dual objectives of this proof of concept study were to evaluate trough effects of tiotropium (TIO) or aclidinium (ACL) when used as triple therapy and to assess if impulse oscillometry (IOS) might be more sensitive than spirometry in detecting subtle differences in bronchodilator response.. Patients with moderate to severe COPD already taking ICS/LABA were randomized to receive add-on therapy in cross-over fashion with either TIO 18 µg od or ACL 322 µg bid for 2-3 weeks each. Measurements of IOS, spirometry, 6-min walk test, St George's Respiratory Questionnaire (SGRQ) and Baseline/Transition Dyspnoea Index (TDI) were made at baseline and after chronic dosing at trough (12 h for ACL and 24 h for TIO), in addition to domiciliary diurnal spirometry.. 13 patients were completed: mean age 69 years, FEV1 52 % predicted, FEV1/FVC 0.48, and R5 202 % predicted. There were no differences in any visit-based trough IOS or spirometry outcomes comparing TIO versus ACL. Resonant frequency but not total airway resistance at 5 Hz (R5) significantly improved from baseline with both treatments while peripheral airway resistance (R5-R20) significantly improved with ACL. Visit-based FEV1, and forced and relaxed vital capacity were also significantly improved from baseline with both treatments. There were no significant differences in diurnal FEV1 and FEV6 profiles between treatments. 6-min walk distance and post-walk fatigue significantly improved from baseline with ACL, while post-walk dyspnea improved with TIO. SGRQ symptom score significantly improved to a similar degree with both treatments. TDI significantly improved with ACL versus TIO by 1.54 units.. We observed comparable bronchodilator efficacy at trough with TIO and ACL when used as triple therapy in COPD, while IOS was no more sensitive than spirometry.

Topics: Adult; Aged; Aged, 80 and over; Airway Resistance; Bronchoconstriction; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Exercise Test; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Oscillometry; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scotland; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes; Vital Capacity

This was a one-year, Phase III randomized, double-blind, parallel-group, active-control study investigating the long-term safety and tolerability of twice-daily aclidinium 400 μg/formoterol 12 μg versus formoterol 12 μg.. Eligible patients were male or female, current or ex-smokers (history of ≥10 pack-years) aged ≥40 years with a diagnosis of moderate to severe chronic obstructive pulmonary disease (COPD): post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <70%, and post-bronchodilator FEV1≥30% and <80% predicted. Patients were randomized 2:1 to twice-daily aclidinium 400 μg/formoterol 12 μg or formoterol 12 μg, administered via a multidose dry powder inhaler (Genuair™/Pressair(®))(1). The objective was to evaluate the one-year safety of aclidinium 400 μg/formoterol 12 μg versus formoterol 12 μg.. All 590 patients were included in the safety population; 392 patients received aclidinium 400 μg/formoterol 12 μg and 198 patients received formoterol 12 μg. Of these, 581 patients were included in the intent-to-treat (ITT) population (385 patients received aclidinium 400 μg/formoterol 12 μg; 196 patients received formoterol 12 μg). In the safety population, the percentage of patients with ≥1 treatment-emergent adverse event was similar between aclidinium 400 μg/formoterol 12 μg (71.4%) and formoterol 12 μg (65.7%). Mean baseline post-bronchodilator FEV1 was 51.3% of predicted (ITT population). Aclidinium 400 μg/formoterol 12 μg significantly improved morning pre-dose (trough) FEV1 and trough FVC versus formoterol 12 μg at each assessment, with improvements at Week 1 (least squares mean difference [LSMD]: 87.4 mL and 157.8 mL, respectively) maintained at study end (LSMD: 81.5 mL and 185.4 mL, respectively).. Aclidinium 400 μg/formoterol 12 μg was well tolerated, with a safety profile similar to formoterol 12 μg and consistent with that seen in two Phase III studies. Additionally, aclidinium 400 μg/formoterol 12 μg improved lung function versus formoterol 12 μg, with a sustained effect over one year.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Drug Tolerance; Dry Powder Inhalers; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Smoking; Treatment Outcome; Tropanes; Vital Capacity

Preclinical studies suggested that aclidinium and glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400µg, glycopyrronium 50μg and tiotropium 18µg and FEV1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10nM to 1µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV1 after inhalation of aclidinium, glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5min) and glycopyrronium (17.9±10.4min) enhanced 15% FEV1 more rapidly than tiotropium (42.5±19.4min), with no significant difference (P>0.05). In isolated airways, glycopyrronium elicited a dose-dependent onset of action (10nM: 8.2±1.3min, 100nM: 7.1±2.1min, 1μM: 3.4±0.4min) that was faster compared to that induced by aclidinium (1μM: 6.4±0.5min) and tiotropium (1μM: 8.4±1.1min) (P<0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients.

Topics: Administration, Inhalation; Bronchi; Bronchoconstriction; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; In Vitro Techniques; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT).. Patients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 ≥30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg, aclidinium 400 μg, formoterol 12 μg or placebo via Genuair™/Pressair®. Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed.. The pooled intent-to-treat population included 3394 patients. Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies (all p < 0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo (p < 0.01) and aclidinium (p < 0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo (all p < 0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium (p < 0.01).. Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo.. NCT01462942 and NCT01437397 (ClinicalTrials.gov).

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Anticholesteremic Agents; Disease Progression; Double-Blind Method; Drug Combinations; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Time Factors; Tropanes

Aim of our study was to understand if the interaction between aclidinium and formoterol administered at therapeutic doses leads to a synergistic rather than additive broncholytic effect. We tested the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. The analysis of the interaction between aclidinium and formoterol in vitro was measured by applying the Unified Theory, whereas that in COPD patients was measured by applying the Bliss Independence criterion. Aclidinium and formoterol administered alone completely relaxed human isolated bronchial tissues sub-maximally pre-contracted with ACh in a concentration-dependent manner with similar potency (EC50: aclidinium 4.64 ± 0.78 nM, formoterol 2.71 ± 0.21), whereas the interaction of aclidinium plus formoterol produced moderate to strong synergism. Changes in FEV1 values showed that inhaled aclidinium and formoterol induced a significant and time-dependent bronchodilatory effect during the study time. The inhalation of aclidinium and formoterol in combination significantly anticipated at 5 min post-administration the bronchodilatory effect of FEV1, compared with the effect of drugs administered alone. There was a synergistic interaction for FEV1 at 5 min and from 120 min to 240 min post-inhalation, whereas from 30 min to 60 min post-administration the drug interaction was additive. This study shows that aclidinium and formoterol can produce a significant synergistic interaction that may have a role also in the clinic setting.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Bronchi; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Single-Blind Method; Translational Research, Biomedical; Tropanes

Aclidinium bromide ('aclidinium') is a novel, inhaled long-acting muscarinic antagonist. Therapeutic effects of aclidinium on chronic obstructive pulmonary disease (COPD) have been demonstrated in Caucasian populations in several clinical trials. This was a randomized, double-blind, multi-centre phase-3 clinical trial to evaluate the efficacy and safety of aclidinium in a Korean population.. A total of 263 Korean patients with moderate-to-severe COPD were randomized to receive aclidinium (400 μg, bd) (Genuai) or placebo via a dry-powder inhaler. The primary end point was change in trough forced expiratory volume in one second (FEV1 ) at 12 weeks. Other lung function measurements, COPD exacerbation, health status (St George's Respiratory Questionnaire (SGRQ), dyspnoea (Transition Dyspnea Index (TDI) and safety were assessed throughout the study period.. A significant improvement in trough FEV1 from baseline was shown with aclidinium compared with the placebo (0.126 L, P < 0.0001). Significant improvements were also demonstrated in peak FEV1 (0.190 L, P < 0.0001), SGRQ and TDI. Furthermore, aclidinium significantly reduced the prevalence of exacerbations (aclidinium, 5.4%; placebo, 15.6%, P < 0.05), and the duration of exacerbations was shorter compared with placebo (rate ratio: 0.27; P < 0.05). Aclidinium (400 μg) was well tolerated and the prevalence of adverse events was comparable with the placebo.. Inhaled aclidinium (400 μg) was shown to be safe and efficacious in Korean patients with moderate-to-severe COPD.. NCT01636401 at Clinicaltrials.gov.

Topics: Aged; Bronchodilator Agents; Delayed-Action Preparations; Disease Progression; Double-Blind Method; Dry Powder Inhalers; Dyspnea; Female; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Republic of Korea; Severity of Illness Index; Tropanes

Standard spyrometric assessment in chronic obstructive pulmonary disease (COPD) only evaluates bronchial obstruction. However, airflow limitation and hyperinflation are the main pathophysiological factors responsible for dyspnoea and reduced exercise tolerance in patients with COPD. This study evaluated the effects of aclidinium bromide 400 μg and glycopyrronium bromide 50 μg on these parameters. Patients with stable severe/very severe COPD were randomized in this double-blind, double-dummy, crossover, Phase IV study. Patients received single doses of each drug on separate days. Primary endpoints were changes in residual volume (RV) and intra-thoracic gas volume (ITGV), assessed by full-body plethysmography. Other endpoints included changes variations in lung ventilation inhomogeneity (Phase III slope of single-breath nitrogen washout test, SBN2), dyspnoea visual analogue scale, and pulmonary specific total airway resistances. Assessments were performed at baseline and 5, 15, 30, 60, and 180 min post-administration. Thirty-seven patients were randomized (31 male; mean age 71 years). Aclidinium and glycopyrronium significantly improved ITGV versus baseline at all-time points (p < 0.05). Significant improvements in RV were observed after 5 min with aclidinium and after 60 min with glycopyrronium. RV improvements were significantly greater with aclidinium than glycopyrronium from 5 to 60 min post-administration (p < 0.05). Both treatments improved dyspnoea versus baseline at all-time points (p < 0.05). Aclidinium significantly improved ventilation inhomogeneity versus baseline at all-time points; no significant changes were observed for glycopyrronium. For the first time two long-acting muscarinic antagonists have been compared in acute conditions with body plethysmography and SBN2 test. We demonstrated that both aclidinium and glycopyrronium significantly reduce hyperinflation and dyspnoea in severe and very severe COPD patients. Aclidinium however promoted a faster reduction in RV and was the only able to reduce lung ventilation inhomogeneity. Trial Registration numbers available on Clinicaltrials.gov: NCT02181023.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Dyspnea; Endpoint Determination; Female; Glycopyrrolate; Humans; Lung; Male; Middle Aged; Plethysmography; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Residual Volume; Respiratory Function Tests; Tropanes

The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU) or the EXAcerbations of Chronic pulmonary disease Tool (EXACT) were compared prospectively in a 24-week, phase III trial (ATTAIN). Patients with moderate-to-severe chronic obstructive pulmonary disease received twice-daily aclidinium 200 μg, aclidinium 400 μg or placebo. All HCRU events were reported to physicians. "EXACT-identified" events were categorised as "EXACT-reported" (detected by EXACT and reported to the physician) and "EXACT-unreported" (detected but not reported). Health status was measured using the St George's Respiratory Questionnaire (SGRQ). Annualised EXACT-identified event rates were higher in all study arms (placebo 1.39, aclidinium 200 μg 1.00 and aclidinium 400 μg 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 μg 0.43 and aclidinium 400 μg 0.40 per patient per year). Concordance between methods was low (kappa 0.16). Aclidinium reduced EXACT-identified events (rate ratio versus placebo: aclidinium 200 μg 0.72 and aclidinium 400 μg 0.71; both p<0.05); HCRU events were similarly reduced. At week 24, SGRQ scores improved (-6.6 versus baseline) in patients with no event during weeks 1-12; improvements were significantly smaller in patients with HCRU events (-3.4; p=0.036) or EXACT-unreported events (-3.0; p=0.002). Unreported events were more frequent than reported events. Both had similar negative impact on health status. Aclidinium reduced the frequency of both types of event.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Surveys and Questionnaires; Treatment Outcome; Tropanes

Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed.. In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a.. At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy.. Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD.. ClinicalTrials.gov: NCT01462942.

Topics: Aged; Double-Blind Method; Drug Combinations; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Tropanes; Vital Capacity

This study evaluated the effects of aclidinium bromide, a long-acting muscarinic antagonist indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD), on exercise endurance, dyspnea, lung hyperinflation, and physical activity.. In this randomized, double-blind, crossover study, patients with stable COPD and moderate-to-severe airflow limitation received aclidinium 400 μg twice daily or placebo via Genuair®/Pressair(®a) for 3 weeks (2-week washout between treatment periods). The primary endpoint was change from baseline to Week 3 in endurance time, measured by constant work rate cycle ergometry testing at 75% peak incremental work rate. Changes from baseline in intensity of exertional dyspnea (Borg CR10 Scale®) and trough inspiratory capacity were secondary endpoints. Additional endpoints included changes from baseline in other spirometric, plethysmographic, and physical activity (assessed by objective accelerometer measurement) parameters. Efficacy endpoints were analyzed using an analysis of covariance model.. In total, 112 patients were randomized and treated (mean age 60.3 years; mean post-bronchodilator forced expiratory volume in 1 s 1.7 L [56.7% predicted]; mean endurance time 485.7 s). After 3 weeks, endurance time was significantly increased with aclidinium versus placebo (treatment difference 58.5 s; p < 0.05). At Week 3, aclidinium significantly reduced dyspnea intensity at isotime during exercise (treatment difference -0.63; p < 0.05) and improved trough inspiratory capacity (treatment difference 78 mL; p < 0.05) versus placebo. Significant improvements in spirometric, plethysmographic, and some physical activity parameters were observed with aclidinium versus placebo.. These results suggest that aclidinium significantly improves exercise endurance, exertional dyspnea, hyperinflation, and physical activity in patients with COPD.. ClinicalTrials.gov identifier: NCT01471171; URL: http://www.clinicaltrials.gov.

Topics: Accelerometry; Aged; Cross-Over Studies; Double-Blind Method; Dyspnea; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Motor Activity; Muscarinic Antagonists; Physical Endurance; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.. In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed.. At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.. Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.. Clinicaltrials.gov NCT01437397.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Australia; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Dry Powder Inhalers; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Health Status; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; New Zealand; North America; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Time Factors; Treatment Outcome; Tropanes

This was a 52-week, double-blind, extension study in which COPD patients previously treated with twice-daily (BID) aclidinium bromide 200 μg or 400 μg during a 12-week lead-in study (ACCORD COPD I) continued the same treatment, while patients previously receiving placebo were rerandomized (1:1) to aclidinium 200 μg or 400 μg BID. The primary objective of this study was to evaluate the long-term safety and tolerability of aclidinium treatment. Efficacy outcomes included bronchodilation, health status, and rescue medication use. A total of 467 patients completed the lead-in study and 291 patients consented to participate in the extension. At study end, the percentages of patients who reported a treatment-emergent adverse event (TEAE) were similar for both treatments (200 μg, 77.4%; 400 μg, 73.7%). Incidence of anticholinergic TEAEs was low and similar for both treatments, with dry mouth reported in only 1 patient (400 μg). Cardiac TEAEs were reported by a similarly low percentage of patients (<5% for any event in any group) with no apparent dose dependence. Improvements from baseline in lung function were greatest for patients who received continuous aclidinium treatment and those who were rerandomized from placebo to aclidinium 400 μg; these improvements were generally sustained throughout the study. Health status and overall rescue medication use was improved from baseline for both treatments. The safety profile of twice-daily aclidinium and sustained improvements in lung function and health status throughout the 52-week extension study support its use as a long-term maintenance treatment for patients with COPD. (Clinical trial registration number NCT00970268).

Topics: Acute Coronary Syndrome; Aged; Atrioventricular Block; Bundle-Branch Block; Creatine Kinase; Disease Progression; Double-Blind Method; Drug Eruptions; Dyspnea; Female; gamma-Glutamyltransferase; Headache; Health Status; Heart Failure; Humans; Hypertension; Maintenance Chemotherapy; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Stroke; Tropanes; Xerostomia

This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).. Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0-24) at week 6. Secondary and additional endpoints included FEV1 AUC12-24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety.. Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0-24 and FEV1 AUC12-24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group.. Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated.

Topics: Aged; Area Under Curve; Bronchodilator Agents; Circadian Rhythm; Cough; Disease Progression; Double-Blind Method; Dry Powder Inhalers; Dyspnea; Female; Forced Expiratory Volume; Headache; Humans; Male; Middle Aged; Muscarinic Antagonists; Patient Preference; Pharyngitis; Pulmonary Disease, Chronic Obstructive; Respiratory Sounds; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Tropanes; Xerostomia

Aclidinium is a novel, long-acting muscarinic antagonist indicated for maintenance treatment of COPD.. In this 52-week, parallel-group, double-blind study, patients with moderate-to-severe COPD were randomized (1:1) to receive aclidinium twice-daily (BID) 200 μg or 400 μg via a novel, dry powder inhaler (Genuair(®)/Pressair(®)) [Registered trademarks of Almirall, SA, Barcelona, Spain for use within the European Union, Iceland, Norway, and Switzerland as Genuair(®) and within the United States as Pressair(®)]. Safety, the primary objective, was assessed via adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead electrocardiograms. Efficacy was evaluated using spirometry, SGRQ, and rescue medication use.. A total of 605 patients were randomized in the study. The percentage of patients reporting any treatment-emergent AE (TEAE) was comparable between groups; most TEAEs were mild or moderate. Anticholinergic TEAEs were reported by low percentages of patients in either treatment group (dry mouth: 200 μg, 1.3%; 400 μg, 2.7%; constipation: 200 μg, 2.9%; 400 μg, 1.7%). Cardiac TEAEs were also reported by a low percentage of patients (<2% for any event in any group) and did not appear to be dose dependent. There were no clinically relevant abnormalities in other safety outcomes. Both aclidinium 200 μg and 400 μg resulted in improvements from baseline to Week 52 in FEV1, with numerically greater increases observed with the higher dose. Clinically important improvements in SGRQ scores and a reduction in rescue medication use were observed throughout the study for both doses.. Long-term treatment with aclidinium 200 μg or 400 μg BID was well tolerated, with sustained benefits in lung function and health status in patients with COPD throughout the 1-year study.

Topics: Administration, Inhalation; Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Repositioning; Dry Powder Inhalers; Female; Forced Expiratory Volume; Health Status; Heart Diseases; Humans; Long-Term Care; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 μg in patients with moderate-to-severe COPD.. In this double-blind study, 544 patients with COPD were randomized to placebo or twice-daily aclidinium 200 or 400 μg administered by Genuair(®)/Pressair(®). Lung function, health status [measured by the St. George's Respiratory Questionnaire (SGRQ)], dyspnea [measured using the Transition Dyspnea Index (TDI)], and safety were assessed throughout the study.. Mean changes from baseline in morning trough forced expiratory volume in 1 s (FEV(1)) at week 12 (primary endpoint) were significantly higher for aclidinium than for placebo (200 μg, 51 mL; 400 μg, 72 mL; both p < 0.05). Aclidinium also significantly improved other lung function outcomes. At week 12, improvements from baseline were observed with aclidinium in SGRQ total score (200 μg, -6.0; 400 μg, -5.4) and TDI focal score (200 μg, 1.0; 400 μg, 1.3). Furthermore, clinically important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients, respectively, who received aclidinium 400 μg, with a significant difference versus placebo for TDI (p < 0.05). Anticholinergic-related adverse events (e.g., dry mouth) were infrequent, occurring <2 % for any event in any treatment group. Both aclidinium doses were well tolerated.. This study demonstrates efficacy and safety of aclidinium in COPD patients. Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study.

Topics: Aged; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Placebos; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Tropanes

Aclidinium bromide is a long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease treatment. This 2-part, phase I study evaluated the safety and tolerability of single ascending intravenous (IV) doses of aclidinium to determine its maximum tolerated dose (MTD; part I) and its absolute bioavailability (part II). Healthy male participants (N = 24) were randomized (1:1) in each part: 3-period crossover, placebo-controlled, single-ascending, alternating IV doses of aclidinium (25-400 µg) in part I and 2-period crossover, single-alternating IV and inhaled doses of aclidinium (200 µg) in part II. A ≥7-day washout separated treatment periods. Pharmacokinetic data were collected in both parts. Following IV or inhaled aclidinium, time to reach maximum plasma concentration following drug administration (t(max) ) was 5 to 7 minutes for all doses. After maximum plasma drug concentration (C(max)), aclidinium was rapidly cleared from plasma. Aclidinium absolute bioavailability was <5% following a single inhaled 200-µg dose. Urinary excretion of unchanged aclidinium was very low, with a greater amount of inactive metabolites excreted compared with aclidinium, all of which were recovered within 12 hours postdose. The MTD following IV administration was not reached; all single IV (25-400 µg) and inhaled doses (200 µg) were well tolerated. In conclusion, the low and short-lived bioavailability of aclidinium and the low incidence of systemic side effects contribute to its positive safety and tolerability profile.

Topics: Administration, Inhalation; Adult; Biological Availability; Biotransformation; Blood; Cross-Over Studies; Dose-Response Relationship, Drug; Half-Life; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Single-Blind Method; Tropanes; Urine; Young Adult

The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD.. In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 μg bid, tiotropium 8 μg once daily, and placebo for 15 days, with a 9- to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV(1) AUC(0-12/12h) (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0-12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), peak FEV(1), and COPD symptom scores.. Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV(1) AUC(0-12/12h) at day 15 was significantly greater for aclidinium and tiotropium over placebo (P < .0001). Mean changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), and peak FEV(1) at day 15 were significantly greater for aclidinium and tiotropium over placebo (P < .0001 for all except P < .001 for FEV(1) AUC(12-24/12h) tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1) as well as on day 15 for FEV(1) AUC(12-24/12h) (P < .05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P < .05) but not with tiotropium.. In patients with COPD, aclidinium 400 μg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg bid on bronchodilation and COPD symptoms.. ClinicalTrials.gov; No.: NCT00868231; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; 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; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Tropanes

This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD.. In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV₁ and peak FEV₁ at Week 12, respectively. Health status (St. George's Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed.. A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV₁ of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV₁ compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV₁ by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%-1.6%; constipation: 0%-1.1%).. Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo.. This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as "Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)".

Topics: Administration, Inhalation; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Spirometry; Surveys and Questionnaires; Treatment Outcome; Tropanes

The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 μg or 400 μg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV(1)) at week 24. Other end-points included peak FEV(1), health status (St George's Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI). Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV(1) (99 and 128 mL; both p<0.0001) and peak FEV(1) (185 and 209 mL; both p<0.0001). Peak FEV(1) improvements on day 1 were comparable with week 24. Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p<0.001 and p<0.0001) and TDI focal score (0.6 and 1.0 units; p<0.05 and p<0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo. Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyspnea; Female; Forced Expiratory Volume; Health Status; Humans; Male; Metered Dose Inhalers; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Treatment Outcome; Tropanes

This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 μg, 200 μg, 400 μg (via Genuair®*), formoterol 12 μg (via Aerolizer®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV1) normalised area under the curve (AUC)0-12 on Day 7. Secondary endpoints were: change from baseline in FEV1 normalised AUC12-24, FEV1 normalised AUC0-24 and morning pre-dose FEV1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV1 normalised AUC0-12 vs placebo (p<0.0001). FEV1 normalised AUC12-24, FEV1 normalised AUC0-24, and morning pre-dose FEV1 were also statistically significantly greater with all aclidinium doses vs placebo (p<0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 μg vs 100 μg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 μg and 400 μg as suitable doses for further investigation in Phase III trials.

Topics: Administration, Inhalation; Aged; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

To investigate the pharmacokinetics, safety and tolerability of aclidinium bromide 200 μg and 400 μg after a single dose and repeated once-daily doses in younger and elderly patients with moderate or severe chronic obstructive pulmonary disease (COPD).. Younger (40-59 years; n = 12) and elderly (≥ 70 years; n = 12) patients were treated with aclidinium via the Genuair® inhaler. Patients received once-daily aclidinium 200 μg for 3 days; after a 7-day washout period, patients received once-daily aclidinium 400 μg for 3 days. Pharmacokinetic analyses were conducted on plasma and urine on Days 1 and 3 of both treatment periods. Safety and tolerability were assessed.. Aclidinium showed similar linear and time-independent pharmacokinetics in younger and elderly patients at each dose level and day of treatment. For both age groups at each dose level and day, aclidinium appeared rapidly in the plasma with a median tmax between 10 and 15 min; concentrations of aclidinium in the plasma declined rapidly with a t1/2 between 1 and 3 h. Plasma exposure with the 400 μg dose was ~ 2-fold higher than for the 200 μg dose in both age groups on both days. For both age groups, urinary excretion of aclidinium over 24 h was < 0.15% of the dose at each dose and day. Aclidinium 200 μg and 400 μg were safe and well tolerated in both age groups.. These data suggest that no dose adjustment of aclidinium is required when treating elderly patients with COPD.

Topics: Adult; Age Factors; Aged; Area Under Curve; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes

Static and dynamic lung hyperinflation are associated with exercise impairment and poor outcomes in COPD patients. Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist currently in development for COPD treatment.. Patients with moderate to severe COPD (N = 181) were randomized to once-daily aclidinium 200 μg or placebo for 6 weeks. Constant work rate cycling exercises at 75% of peak work rate were performed at baseline, Day 1, Week 3, and Week 6. The primary efficacy measure was change in exercise endurance time (ET) from baseline to Week 6. Secondary outcomes included changes in trough forced expiratory volume in 1 s (FEV(1)), inspiratory capacity (IC), IC/total lung capacity (TLC), and functional residual capacity (FRC) from baseline to Day 1, Week 3, and Week 6. Borg dyspnea scores during exercise, locus of symptom limitation, and safety measures were assessed.. Aclidinium significantly improved ET on Day 1 (P = 0.0002), and improvements were sustained through Week 3 (P = 0.0007) and Week 6 (P = 0.0042) vs placebo. Compared with placebo, aclidinium improved trough FEV(1), IC, and IC/TLC at Weeks 3 and 6 (P < 0.05 for all). Exertional dyspnea scores at isotime were reduced on Day 1, Week 3, and Week 6 for aclidinium vs placebo (P < 0.05). Furthermore, the likelihood of stopping exercise due to breathing discomfort was lower in the aclidinium group at study end (P = 0.0208) compared with placebo. No differences in safety outcomes were reported between treatments.. Aclidinium significantly increased exercise tolerance, improved airflow obstruction and lung hyperinflation, and was safe and well tolerated. REGISTRATION OF TRIAL: This trial was registered with ClinicalTrials.gov (NCT00500318) under the name "A Study of Exercise Endurance and Lung Hyperinflation in Patients with Moderate to Severe COPD".

Topics: Bronchodilator Agents; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Treatment Outcome; Tropanes; Vital Capacity

The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).. In two double-blind, 52-week studies, ACCLAIM/COPD I (n=843) and II (n=804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1<80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.. At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p<0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p<0.001). More patients had a SGRQ improvement≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p=0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p=0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p=0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p=0.9). Adverse events were minor in both studies.. Aclidinium is effective and well tolerated in patients with moderate to severe COPD.. ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Dry Powder Inhalers; Dyspnea; Europe; Female; Forced Expiratory Volume; Health Status; Humans; Logistic Models; Lung; Male; Middle Aged; Muscarinic Antagonists; North America; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome; Tropanes

Aclidinium bromide is a novel, long-acting, muscarinic antagonist in phase III development for the maintenance treatment of COPD. This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies. A total of 464 patients with moderate to severe stable COPD were randomised to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400microg), placebo, or open-label tiotropium (18microg) for 4 weeks. Spirometric measurements were performed at 22-24h after the first dose and then at weekly intervals, and from 0.5 to 6h post-dose on day 1 and day 29. Compared with placebo, aclidinium 200microg and 400microg significantly increased trough FEV(1) on day 29 versus baseline. During the first 6h post-dose, the bronchodilatory effect of aclidinium (all doses) on day 1 was comparable to that on day 29. Time to peak FEV(1) was 3h for aclidinium 100-400microg. Aclidinium was well tolerated, with no dose-dependent effect on ECG, laboratory parameters, or adverse events. The incidence of AEs was generally comparable to placebo. Aclidinium produced sustained bronchodilation over 24h and was well tolerated during this short-term study. Based on these data, aclidinium 200microg was selected as the investigational dose for future clinical trials in COPD.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tropanes; Vital Capacity

Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist bronchodilator currently in Phase III clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacodynamics, pharmacokinetics, safety and tolerability of ascending doses of aclidinium bromide in patients with COPD.. This double-blind, randomised, placebo-controlled, crossover study was conducted in patients with moderate to severe COPD (forced expiratory volume in 1s [FEV(1)] <65% predicted). Patients were randomly assigned to one of four treatment sequences of aclidinium bromide 100, 300, 900microg and placebo with a washout period between doses. The primary outcome was area under the FEV(1) curve over the 0-24h time interval.. Seventeen patients with COPD were studied. Mean FEV(1) over 24h was 1.583L for placebo, and 1.727L, 1.793L and 1.815L for aclidinium bromide 100, 300 and 900microg, respectively (p<0.001 vs. placebo, all doses). Significant changes from baseline in FEV(1) were detected 15min post-dose for aclidinium bromide 300 and 900microg, with a peak effect 2h post-dose (all doses). Aclidinium bromide was undetected in plasma. The majority of adverse events was unrelated to study medication and did not result in discontinuation.. Aclidinium bromide 100-900microg produced sustained bronchodilation over 24h in patients with COPD.

Topics: Bronchodilator Agents; Epidemiologic Methods; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes

Aclidinium bromide is a muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This phase I trial in healthy subjects investigated the bronchodilator activity of aclidinium and its ability to reduce methacholine-induced bronchoconstriction.. This double-blind, partial-crossover study randomized 12 subjects to treatment with single doses of aclidinium (50, 300 or 600 microg) or placebo. Drug activity was assessed for 24 h after administration by specific airway conductance (sGaw), airways resistance (Raw) and bronchial responsiveness (PC35 sGaw methacholine).. Aclidinium significantly increased sGaw compared with placebo at all assessments and doses (sGaw mean +/- SD AUC (l kPa(-1) h) for placebo 24.4 +/- 4.37, for 50 microg 29.0 +/- 7.08, for 300 microg 31.2 +/- 6.68 and for 600 microg 32.7 +/- 7.95) (P < 0.009), except 50 microg at 1 and 24 h. Significant decreases in Raw were observed with aclidinium 300 and 600 microg compared with placebo at all assessments (Raw mean +/- SD AUC (kPa s(-1) l(-1) h) for placebo 7.7 +/- 3.46, for 300 microg 5.8 +/- 2.33, for 600 microg 6.3 +/- 3.11) (P < 0.04) except 600 microg at 24 h. Differences between aclidinium 300 and 600 microg vs. placebo in PC35 doubling concentration were significant at all assessments (mean +/- SD AUC (mg ml(-1) h) for placebo 100.0 +/- 30.27, for 50 microg 117.2 +/- 33.33, for 300 microg 168.9 +/- 28.66 and for 600 microg 179.1 +/- 15.73 (P < 0.0001). For all endpoints, there was a significant difference between aclidinium 50 microg and the higher doses (P < 0.0001). Aclidinium was not detected in plasma and was well tolerated.. Aclidinium produced statistically significant and sustained bronchodilation over 24 h, suggesting long-acting efficacy and providing a rationale for future studies in patients with COPD.

Topics: Administration, Inhalation; Adolescent; Adult; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tropanes; Young Adult

ABSTRACT Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the rate of onset of bronchodilation with aclidinium compared with placebo and tiotropium. This was a double-blind, double-dummy, multicenter, crossover study in COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) ≥30% and <60% predicted. On study days, patients received single doses of aclidinium 200 μg, tiotropium 18 μg, or placebo. Serial spirometry was conducted from 10 minutes to 3 hours post-dose. The primary variable was the percentage of patients with an increase in FEV(1) of ≥10% above baseline at 30 minutes post-dose. Other assessments included change from baseline in FEV(1) and dyspnea over 3 hours post-dose. A total of 115 patients entered the study. Significantly more patients had an increase in FEV(1) of ≥10% above baseline at 30 minutes with aclidinium and tiotropium versus placebo (49.5% and 51.8% versus 13.8%; p < 0.0001). At 30 minutes, the relative increase from baseline in FEV(1) was significantly higher for aclidinium and tiotropium versus placebo (12% and 11% versus 3%; p < 0.0001). Aclidinium and tiotropium also significantly increased FEV(1) (p < 0.01) and improved the perception of dyspnea compared with placebo at all measured time points from 10 minutes to 3 hours post-dose. In conclusion, aclidinium provided effective bronchodilation, similar to that seen with tiotropium, with significant improvements compared with placebo observed from 10 minutes post-dose.

Topics: Administration, Inhalation; Bronchodilator Agents; 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; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

Aclidinium bromide is an inhaled, long-acting muscarinic antagonist currently in development for the treatment of chronic obstructive pulmonary disease. Renal impairment may affect drug clearance.. This study was conducted to evaluate the pharmacokinetic (PK) parameters, safety, and tolerability of aclidinium bromide and its metabolites in patients with normal and impaired renal function to determine whether dosing adjustments are required when renal dysfunction is present.. This was a Phase I, open-label, single-center, single-dose clinical trial conducted in Munich, Germany. Adults with varying degrees of renal function were assigned to 4 groups (n = 6 for each) based on creatinine clearance, including normal renal function (>80 mL/ min), mild renal insufficiency (>50-≤80 mL/min), moderate renal insufficiency (>30-≤50 mL/min), and severe renal insufficiency (<30 mL/min). Single doses of aclidinium bromide 400 μg were administered using a multidose dry powder inhaler. Blood and urine samples were obtained before dosing and at various time points up to 48 hours after dosing to analyze the PK parameters of aclidinium bromide and its metabolites. Plasma PK Parameters were AUC₀₋(t), MJC₀₋(∞) C(max), T(max), t(½) CL/F and apparent volume of distribution during the terminal phase Xz; urinary parameters were the amount of aclidinium or acid or alcohol metabolite excreted in urine, the percentage of the dose excreted in urine (fe), and renal clearance (CL(R)). Tolerability was assessed using physical examination, vital signs, 12-lead ECG recordings, laboratory tests, and adverse-event (AE) reports. The Wilcoxon rank sum test was used to compare the median PK values between the normal and impaired renal function groups. Pearson correlation coefficients and linear regression models were used to analyze the relationship between creatinine clearance and AUC₀₋(∞) and between creatinine clearance and CL(R) for aclidinium and its metabolites.. A total of 16 men and 8 women were included in the study. All participants were white; mean (SD) age was 55 (10.7) years and weight was 70.8 (9.2) kg. Aclidinium Cmax was observed in plasma by 5 minutes after dosing (ie, median Tmax) and did not differ significantly among the renal function groups. Plasma concentrations of aclidinium declined after reaching Cmax, with median t(½) values ranging from 2.07 to 4.18 hours across all renal function groups. Most of the individual t(½) values were between 1.5 and 3.5 hours, regardless of the degree of renal insufficiency. No significant relationship between AUC₀₋(∞)) and creatinine clearance was observed (Pearson correlation coefficient = -0.0446; P = NS). Urinary excretion of aclidinium was very low, with a mean 0.090% (median 0.078%) of the dose recovered from the urine in participants with normal renal function. Eight AEs were reported in 7 participants after drug administration; all were mild to moderate in severity and resolved spontaneously. There were no serious drug-related AEs and no deaths.. The plasma PK parameters of aclidinium bromide were not significantly altered after a single inhaled dose of aclidinium bromide 400 μg in this small group of patients with various degrees of impaired renal function. The very low urinary excretion of aclidinium in all renal function groups indicates that renal function plays a minor role in aclidinium plasma clearance. Aclidinium appeared well tolerated in the population studied. These results suggest that aclidinium dose adjustment on the basis of renal function may not be necessary.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Female; Humans; Kidney Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Renal Insufficiency; Severity of Illness Index; Tropanes; Young Adult

Systemic exposure to anticholinergics used for chronic obstructive pulmonary disease (COPD) may lead to side effects. This study assessed safety, tolerability, and pharmacokinetics of multiple doses of aclidinium bromide, a novel, long-acting antimuscarinic. Sixteen healthy participants received aclidinium bromide 200, 400, or 800 microg or placebo by dry-powder inhaler for 5 days, with > or =7 days washout. Aclidinium bromide and metabolite pharmacokinetics were assessed. Aclidinium bromide plasma levels were below the lower limit of quantification (LLOQ: 0.05 ng/mL) after 200 microg and in most participants after 400 microg. Plasma levels in all participants were below the LLOQ at all doses, including the highest dose, beyond 1 hour postdose. AUC(0-t) and C(max) at steady state were, respectively, 0.08 ng.h/mL and 0.12 ng/mL (aclidinium bromide), 0.40 ng.h/mL and 0.14 ng/mL (alcohol metabolite), and 13.47 ng.h/mL and 2.26 ng/mL (acid metabolite). The t(max) for aclidinium bromide 800 microg was 15 minutes (first kinetic time point). Adverse event frequency was comparable between treatment groups and placebo. The most commonly reported adverse events, probably treatment related, were coughing (n = 2) and dysphagia (n = 1); 94% of adverse events were mild. These data suggest a low systemic bioavailability and favorable safety profile for aclidinium bromide with repeated dosing for COPD.

Topics: Administration, Inhalation; Adult; Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes

The Genuair inhaler is a new multidose dry powder inhaler for the delivery of aclidinium bromide - a novel, long-acting, muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to assess the inspiratory flow characteristics through Genuair in patients with moderate or severe COPD. Using a three-period cross-over design, 48 patients were randomised to inhale placebo powder through Genuair, HandiHaler A (slow, deep inhalation as per manufacturer's instructions) or HandiHaler B (fast, forceful inhalation). Three measurements of peak inspiratory flow (PIF), 10min apart, were recorded for each method of administration. The highest and average PIFs for the three attempts (mean+/-standard deviation) generated through the Genuair inhaler were 97.7+/-15.7 and 92.0+/-15.4L/min, respectively. Furthermore, 97% of inhalations with the Genuair inhaler were successful (activation of trigger threshold mechanism) and optimal (PIF> or =45L/min). The highest and average PIFs generated through HandiHaler A and B were significantly lower than with the Genuair inhaler. In conclusion, patients with moderate or severe COPD were able to generate sufficient inspiratory airflow through the Genuair inhaler to reliably inhale the full dose and reset the inhaler.

Topics: Acute Disease; Administration, Inhalation; Aged; Equipment Design; Female; Humans; Male; Metered Dose Inhalers; Middle Aged; Muscarinic Antagonists; Powders; Pulmonary Disease, Chronic Obstructive; Tropanes

Aclidinium bromide was approved in the European Union for the treatment of chronic obstructive pulmonary disease (COPD) in adult patients in 2012 and in a fixed-dose combination with formoterol in 2014. We characterised new users of aclidinium, aclidinium/formoterol and other COPD medications and evaluated off-label prescribing of these medications in three European populations.. We described demographic characteristics, comorbidities, comedications, COPD severity and off-label prescribing of new users of aclidinium, aclidinium/formoterol and other COPD medications in patients with COPD aged ≥ 40 years in the Clinical Practice Research Datalink (CPRD, UK), Danish National Health Databases, and German Pharmacoepidemiological Research Database (GePaRD) between 2015 and 2017.. We included 17,668 new users of aclidinium (CPRD, 4871; Denmark, 2836; GePaRD, 9961) and 14,808 new users of aclidinium/formoterol (CPRD, 2153; Denmark, 2586; GePaRD, 10,069). Study patients were of similar age, except in GePaRD, where users of long-acting beta2-agonists (LABA)/inhaled corticosteroids were younger. Patients had multiple comorbidities and used multiple comedications-most frequently hypertension (50-79%) and short-acting beta2-agonists (26-84%). Aclidinium users in CPRD and long-acting anticholinergics/LABA users in Denmark and GePaRD had the highest frequency of severe/very severe COPD. Off-label prescribing of aclidinium (5.0% [CPRD]-8.9% [Denmark]) and aclidinium/formoterol (2.6% [GePaRD]-3.2% [CPRD]) was low, and the main reason was asthma without a COPD diagnosis.. Aclidinium and aclidinium/formoterol were mostly prescribed according to label, with preference given to older patients with more severe COPD and to patients with a high prevalence of comorbidities and comedication use.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Bronchodilator Agents; Denmark; Formoterol Fumarate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes; United Kingdom

This multicenter, prospective, observational study aimed to supplement real-world evidence on the effects of aclidinium bromide on the quality of life (QoL), symptoms, and activity impairment of patients with COPD.. Eligible patients were ≥40 years of age, newly initiated on aclidinium bromide as monotherapy or add-on therapy according to the product's approved label. Patient-reported COPD assessment test (CAT), the severity of symptoms and their impact on daily activities, and the features of the Genuair. Between 13 March 2015 and 29 January 2016, 285 eligible consenting patients (76.3% males; median age: 69.0 years; 26.0% newly diagnosed with COPD) were enrolled by 15 hospital-based respiratory medicine specialists in Greece. Aclidinium bromide was initiated as add-on therapy to other inhaled maintenance medications in 73.1% of evaluable patients. The median (interquartile range [IQR]) baseline CAT score decreased from 14.0 (9.0-20.0) to 10.0 (6.0-15.0) points (p<0.001) after 12 weeks of treatment, with 76.5% of the patients achieving a ≥2-point decrease. The severity of night-time and early-morning symptoms, assessed using a 5-point Likert-type scale, decreased from a median (IQR) of 1.0 (0.0-2.0) to 0.0 (0.0-1.0), and from 2.0 (1.0-2.0) to 1.0 (1.0-2.0), respectively (p<0.001 for both). In patients with paired data, the prevalence of at least moderate night-time symptoms, early-morning symptoms, and daily activity impairment decreased from 28.2% to 19.1%, from 63.6% to 34.2%, and from 59.5% to 38.7%, respectively (p<0.001 for all). Inhaler device features were assessed as "very good"/"good" by more than 90% of the patients. The adverse drug reaction rate was 1.4%.. The study provides real-world evidence on the beneficial effects of aclidinium bromide on the patients' QoL, symptom severity, and daily activity impairment, which are complemented by a favorable safety profile and high patient satisfaction with the inhaler device.

Topics: Activities of Daily Living; Administration, Inhalation; Aged; Attitude of Health Personnel; Bronchodilator Agents; Female; Functional Status; Greece; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Patient Satisfaction; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Time Factors; Treatment Outcome; Tropanes

To systematically evaluate the efficacy and safety of combined aclidinium bromide and formoterol fumarate for chronic obstructive pulmonary disease (COPD).. Electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Library Central Register of Controlled Trials, WanFang, and China National Knowledge Infrastructure (CNKI) database were searched for studies on the use of combined aclidinium bromide and formoterol fumarate in the treatment of COPD. Two independent researchers performed literature screening, data extraction, and assessment of quality of studies. The strength of the association of the efficacy and safety of combined aclidinium bromide and formoterol fumarate in the treatment of COPD was evaluated according to the odds ratio (OR), mean differences (MDs), and 95% confidence interval (CI). Statistical analysis was carried out via using RevMan 5.3 software.. The results of the present study will be published in a peer-reviewed journal.. The conclusion of the present study will provide evidence to judge whether combined aclidinium bromide and formoterol fumarate is an effective and safety intervention in the treatment of COPD.. INPLASY202070063.

Topics: Bronchodilator Agents; Drug Combinations; Formoterol Fumarate; Humans; Meta-Analysis as Topic; Pulmonary Disease, Chronic Obstructive; Research Design; Systematic Reviews as Topic; Tropanes

Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs.. We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting β2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012-2017).. Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40-0.72) for aclidinium, 0.96 (95% CI, 0.76-1.21) for tiotropium, 0.76 (95% CI, 0.58-0.99) for other LAMA, and 1.08 (95% CI, 0.90-1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22-0.79), which corresponded to 26% of the aclidinium users (<15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71-1.48).. Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Case-Control Studies; Cholinergic Antagonists; Female; Humans; Male; Middle Aged; Mortality; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Risk Factors; Tiotropium Bromide; Tropanes; United Kingdom

To describe and compare demographic and clinical profile of patients newly initiated on aclidinium (ACL) or tiotropium (TIO) and identify factors associated with newly initiated ACL in real-life clinical practice during 2013 in Catalonia.. We performed a population-based, retrospective, observational study with data obtained from the Information System for Research Development in Primary Care, a population database that contains information of 5.8 million inhabitants (more than 80% of the Catalan population). Patients over 40 years old, with a recorded diagnosis of COPD and newly initiated treatment with either ACL or TIO during the study period (January to December 2013), were selected. A descriptive analysis of demographic and clinical characteristics was performed, and treatment adherence was also assessed for both cohorts.. A total of 8,863 individuals were identified, 4,293 initiated with ACL and 4,570 with TIO. They had a mean age of 69.4 years (standard deviation: 11.3), a median COPD duration of 3 years (interquartile range: 0-8), and 71% were males. Patients treated with ACL were older, with more respiratory comorbidities, a longer time since COPD diagnosis, worse forced expiratory volume in 1 second (% predicted), and with a higher rate of exacerbations during the previous year compared with TIO. It was found that 41.3% of patients with ACL and 62.3% of patients with TIO had no previous COPD treatment. Inhaled corticosteroid and long-acting β2-agonist were the most frequent concomitant medications (32.9% and 32.6%, respectively). Approximately 75% of patients were persistent with ACL or TIO at 3 months from the beginning of treatment, and more than 50% of patients remained persistent at 9 months.. Patients initiated with ACL had more severe COPD and were taking more concomitant respiratory medications than patients initiated with TIO. ACL was more frequently initiated as part of triple therapy, while TIO was more frequently initiated as monotherapy.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Databases, Factual; Drug Therapy, Combination; Female; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Severity of Illness Index; Spain; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

Combining in vitro mouth-throat deposition measurements, cascade impactor data and computational fluid dynamics (CFD) simulations, four different inhalers were compared which are indicated for chronic obstructive pulmonary disease (COPD) treatment.. The Respimat inhaler, the Breezhaler, the Genuair, and the Ellipta were coupled to the idealized Alberta throat model. The modeled dose to the lung (mDTL) was collected downstream of the Alberta throat model using either a filter or a next generation impactor (NGI). Idealized breathing patterns from COPD patient groups - moderate and very severe COPD - were applied. Theoretical lung deposition patterns were assessed by an individual path model.. For the Respimat the mDTL was found to be 59% (SD 5%) for the moderate COPD breathing pattern and 67% (SD 5%) for very severe COPD breathing pattern. The percentages refer to nominal dose (ND) in vitro. This is in the range of 44%-63% in vivo in COPD patients who display large individual variability. Breezhaler showed a mDTL of 43% (SD 2%) for moderate disease simulation and 51% (SD 2%) for very severe simulation. The corresponding results for Genuair are mDTL of 32% (SD 2%) for moderate and 42% (SD 1%) for very severe disease. Ellipta vilanterol particles showed a mDTL of 49% (SD 3%) for moderate and 55% (SD 2%) for very severe disease simulation, and Ellipta fluticasone particles showed a mDTL of 33% (SD 3%) and 41% (SD 2%), respectively for the two breathing patterns. Based on the throat output and average flows of the different inhalers, CFD simulations were performed. Laminar and turbulent steady flow calculations indicated that deposition occurs mainly in the small airways. In summary, Respimat showed the lowest amount of particles depositing in the mouth-throat model and the highest amount reaching all regions of the simulation lung model.

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Computer Simulation; Drug Combinations; Dry Powder Inhalers; Equipment Design; Glycopyrrolate; Humans; Hydrodynamics; Lung; Metered Dose Inhalers; Models, Anatomic; Muscarinic Antagonists; Pharynx; Pulmonary Disease, Chronic Obstructive; Respiration; Severity of Illness Index; Tiotropium Bromide; Tropanes

Comparisons of the use of aclidinium bromide and tiotropium bromide for the treatment of chronic obstructive pulmonary disease often concentrate on key end points (exacerbations) at the expense of other benefits and risks. Multicriteria decision analysis (MCDA) can help overcome this by using stakeholder preferences to combine multiple end points into an overall value estimate.. To evaluate the use of aclidinium bromide twice daily via Pressair™ (AstraZeneca Pharmaceuticals LP, Wilmington, DE) and of tiotropium once daily via HandiHaler. Literature reviews and clinician engagement were used to identify value criteria. Performance of criteria was estimated from a clinical trial and clinician opinion. Scores and swing weights came from six clinicians who, during a 2-day workshop, reflected their patients' preferences. Scenario and sensitivity analyses were used to explore uncertainty in model designs and inputs.. Fourteen criteria, covering clinical effectiveness, safety, and convenience of the treatments of chronic obstructive pulmonary disease, were identified. Exacerbations and device preloading were identified as the most important to patients; the least important was rescue medication use. Tiotropium's higher overall clinical effectiveness score was offset by aclidinium's better performance on safety and convenience outcomes. The MCDA generated a -42 (worst performance) to 100 (best performance) scale. The net impact of benefits over risks of aclidinium (38.5) exceeded that of tiotropium (13.2), and patients preferred aclidinium 79.7% of the time.. When considering clinical benefits and risks, aclidinium and tiotropium generate similar value to patients, but when convenience criteria are considered, aclidinium may be preferred. Further work is required to replicate these results, including eliciting preferences directly from patients.

Topics: Administration, Inhalation; Bronchodilator Agents; Forced Expiratory Volume; Humans; Nebulizers and Vaporizers; Patient Preference; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide; Tropanes; United States

We investigated the effect of the long-acting muscarinic antagonist aclidinium bromide on chronic obstructive pulmonary disease (COPD) exacerbations by pooling data from five randomized, placebo-controlled, parallel-group Phase III studies of 3-6 months' duration. Data were pooled from the aclidinium 400 μg twice-daily (BID) and placebo arms (N  =  2,521) and stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) group (A, B, C and D). Results showed that fewer patients experienced ≥1 exacerbation with aclidinium (any severity: 12.5%; moderate to severe: 10.9%) compared with placebo (any severity: 15.7%; moderate to severe: 13.3%) and the odds of experiencing ≥1 exacerbation of any severity were reduced in patients receiving aclidinium (odds ratio  =   0.78, p  =  0.039). Furthermore, aclidinium reduced the rate of exacerbations compared with placebo (any severity: rate ratio  =  0.79, p  =  0.026; moderate to severe: 0.80, p  =  0.044). The time to first exacerbation of any severity was delayed with aclidinium compared with placebo (hazard ratio  =  0.79, p  =  0.026) and there was a numerical delay in time to first moderate-to-severe exacerbation. Finally, the effects of aclidinium on exacerbations versus placebo were greater in patients in GOLD Groups B and D; however, it is of note that only 10.7% of patients were classified in Group A or C. In summary, the results indicate that aclidinium 400 μg BID reduces the frequency of COPD exacerbations compared with placebo and that these effects are greater in symptomatic patients.

Topics: Aged; Clinical Trials, Phase III as Topic; Disease Progression; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Severity of Illness Index; Symptom Flare Up; Time Factors; Tropanes; Vital Capacity

Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD). We evaluated the effect of aclidinium bromide 400 μg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS(™): COPD) scale (formerly EXACT-RS).. Data were pooled from the aclidinium 400 μg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction. Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D. Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed.. Of 1210 patients, 1167 had data available for GOLD classification. Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted. Compared with placebo, aclidinium 400 μg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group. The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 μg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D.. Aclidinium 400 μg BID significantly improved respiratory symptoms regardless of the patients' level of symptoms at baseline. Net treatment benefit was similar in patients with low or high levels of symptoms.. ATTAIN (ClinicalTrials.gov identifier: NCT01001494 ) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397 ).

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Clinical Trials, Phase III as Topic; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Multicenter Studies as Topic; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Recovery of Function; Respiration; Severity of Illness Index; Time Factors; Treatment Outcome; Tropanes

Topics: Comorbidity; Drug Administration Schedule; Drug Combinations; Forced Expiratory Volume; Formoterol Fumarate; General Practice; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tropanes

Patients with chronic obstructive pulmonary disease (COPD) experience respiratory symptoms, which impair quality of life. This pooled analysis of two Phase III studies assessed the impact of aclidinium/formoterol on patients with COPD categorized by symptom status.. Data were pooled from two 24-week, randomized, placebo-controlled studies of twice-daily aclidinium/formoterol 400/12 µg in moderate-to-severe COPD (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]). These post hoc analyses evaluated the efficacy of aclidinium/formoterol versus placebo or monotherapies in patients defined as less/more symptomatic by a) Evaluating Respiratory Symptoms (E-RS™) score ≥10/<10 and b) Baseline Dyspnea Index score <7/≥7. Endpoints included trough and 1-hour morning postdose forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, E-RS total score, early-morning and nighttime symptom severity, early-morning limitation of activities, and exacerbation rate.. Data for 3,394 patients were analyzed (mean age: 63.5 years; 60.5% male). In both definitions of less and more symptomatic patients, aclidinium/formoterol improved 1-hour morning postdose FEV1 from baseline at week 24 versus placebo (P<0.001) and both monotherapies (P<0.05). Aclidinium/formoterol improved trough FEV1 from baseline in both groups versus placebo (P<0.05) and formoterol (P<0.05); improvements were greater in more symptomatic patients. Improvements versus aclidinium were also observed in more symptomatic patients (P<0.05). Aclidinium/formoterol improved dyspnea, early-morning symptom severity, and limitation of activities versus placebo in both less and more symptomatic patients (P<0.001). In more symptomatic patients, aclidinium/formoterol also improved E-RS total score and severity of nighttime symptoms from baseline versus placebo and one or both monotherapies (P<0.05). The rate of moderate/severe exacerbations was reduced with aclidinium/formoterol versus placebo in more symptomatic patients.. Aclidinium/formoterol 400/12 µg provided consistent improvements in bronchodilation and symptoms versus monotherapies and reduced exacerbations versus placebo in more symptomatic patients with moderate-to-severe COPD, regardless of the definition used. Furthermore, patients with a low symptom burden achieved benefits with aclidinium/formoterol versus monotherapies in postdose FEV1, dyspnea, and early-morning symptoms.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Circadian Rhythm; Clinical Trials, Phase III as Topic; Drug Combinations; Exercise Tolerance; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Recovery of Function; Severity of Illness Index; Time Factors; Treatment Outcome; Tropanes

Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect.. Human sputum and blood neutrophils were isolated from healthy individuals (n = 37), patients with stable COPD (n = 52) and those with exacerbated COPD (n = 16). The cells were incubated with corticosteroid fluticasone propionate (0.1 nM-1 μM), aclidinium bromide (0.1 nM-1 μM) or a combination thereof and stimulated with 1 μg of lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1β were measured and the mechanisms of corticosteroid resistance evaluated at the end of the incubation.. The non-neuronal cholinergic system was over-expressed in neutrophils from COPD patients, as evidenced by increases in the expression of muscarinic receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine transporter. Aclidinium bromide demonstrated anti-inflammatory effects on neutrophils from COPD patients, reversing their resistance to corticosteroids. Additive effects of combined aclidinium bromide and fluticasone propionate in blocking M2 receptor levels, inhibiting phosphoinositide 3-kinase-δ and enhancing the glucocorticoid response element transcription factor were demonstrated and were accompanied by an increase in the corticosteroid-induced expression of anti-inflammatory-related genes.. LAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD.

Topics: Aged; Anti-Inflammatory Agents; Bronchodilator Agents; Case-Control Studies; Choline O-Acetyltransferase; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Female; Fluticasone; Humans; Inflammation Mediators; Male; Middle Aged; Muscarinic Antagonists; Neutrophils; Non-Neuronal Cholinergic System; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Sputum; Tropanes; Vesicular Acetylcholine Transport Proteins

Topics: Bronchodilator Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Tropanes

The inhaled long-acting muscarinic antagonist aclidinium bromide has been shown to significantly improve lung function parameters and symptom severity in patients with COPD in randomised placebo- and active-controlled clinical studies. To obtain a comprehensive view of the treatment effects, patient-reported outcomes were investigated in a real-life COPD population in routine clinical practice in Austria.. Multicentre, prospective, non-interventional study in patients with COPD who were newly initiated on treatment with Eklira® Genuair® (aclidinium bromide; recommended dose 400 μg twice daily) as first-line or add-on therapy. Patients were either treatment naïve or switched from other COPD medications. Health-related quality of life by means of the COPD Assessment Test™ (CAT) and symptom-related variables were evaluated at the first visit (baseline) and after approximately 12 weeks of treatment. Features of the inhaler were assessed by patients and physicians at the follow-up visit.. A total of 795 COPD patients (56% male; median age: 64 years) were enrolled and treated. During the observational period, the proportion of patients with at least moderate nighttime symptoms, early-morning symptoms, and limitations in morning activities decreased from 45.0% to 21.4%, from 57.7% to 26.0%, and from 49.9% to 25.3%, respectively. All improvements from baseline in symptom severity and activity limitation were statistically significant (p < 0.0001, all tests). The mean (±SD) frequency of nocturnal awakenings decreased from 1.2 (±1.4) to 0.7 (±1.2) times per night (p < 0.0001). Quality of life improved significantly in patients treated with aclidinium bromide over 3 months compared to baseline (p < 0.0001; mean CAT total score: 18.5 ± 7.5 vs. 13.8 ± 7.3). Up to 90% of the patients and up to 91% of the physicians assessed individual features of the inhaler as 'very good' or 'good'. Aclidinium bromide was well tolerated; 6.9% of the patients reported adverse drug reactions, none of which were serious.. This non-interventional study indicated beneficial effects of Eklira® Genuair® in the treatment of COPD with regard to nighttime and early-morning symptoms, limitation of morning activities, and quality of life under routine conditions. The acceptance of the inhaler device was high, which is a prerequisite to ensure adherence in long-term therapy.

Topics: Administration, Inhalation; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Dry Powder Inhalers; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Self Report; Treatment Outcome; Tropanes

Topics: Administration, Inhalation; Bronchodilator Agents; Drug Administration Schedule; Drug Combinations; Evidence-Based Medicine; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

Topics: Administration, Inhalation; Bronchodilator Agents; Drug Administration Schedule; Drug Combinations; Evidence-Based Medicine; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes

Topics: Administration, Inhalation; Delayed-Action Preparations; Drug Combinations; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Tropanes

Combined muscarinic receptor antagonists and long acting β2-agonists improve symptom control in chronic obstructive pulmonary disease (COPD) significantly. In clinical studies aclidinium bromide achieved better beneficial effects than other bronchodilators; however, the underlying molecular mechanisms are unknown. This study assessed the effect of aclidinium bromide combined with formoterol on COPD lung (n=20) and non-COPD lung (n=10) derived epithelial cells stimulated with TGF-β1+carbachol on: (i) the generation of mesenchymal cells in relation to epithelial cells, (II) extracellular matrix (ECM) deposition, and (iii) the interaction of ECM on the generation of epithelial and mesenchymal cells. TGF-β1+carbachol enhanced the generation of mesenchymal cells, which was significantly reduced by aclidinium bromide or formoterol. The effect of combined drugs was additive. Inhibition of p38 MAP kinase and Smad by specific inhibitors or aclidinium bromide reduced the generation of mesenchymal cells. In mesenchymal cells, TGF-β1+carbachol induced the deposition of collagen-I and fibronectin which was prevented by both drugs dose-dependently. Formoterol alone reduced collagen-I deposition via cAMP, this however, was overruled by TGF-β1+carbachol and rescued by aclidinium bromide. Inhibition of fibronectin was cAMP independent, but involved p38 MAP kinase and Smad. Seeding epithelial cells on ECM collagen-I and fibronectin induced mesenchymal cell generation, which was reduced by aclidinium bromide and formoterol. Our results suggest that the beneficial effect of aclidinium bromide and formoterol involves cAMP affecting both, the accumulation of mesenchymal cells and ECM remodeling, which may explain the beneficial effect of the drugs on lung function in COPD.

Topics: Bronchodilator Agents; Carbachol; Cells, Cultured; Cyclic AMP; Drug Therapy, Combination; Epithelial Cells; Extracellular Matrix; Formoterol Fumarate; Humans; Lung; Muscarinic Antagonists; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Smad Proteins; Transforming Growth Factor beta1; Tropanes

Long-acting muscarinic antagonists are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of long-acting muscarinic antagonists have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS). We investigated the effects of aclidinium bromide on pulmonary function, airway remodeling, and lung inflammation in a CS-exposed model of COPD. A total of 36 guinea pigs were exposed to CS and 22 were sham exposed for 24 weeks. Animals were nebulized daily with vehicle, 10 μg/ml, or 30 μg/ml aclidinium, resulting in six experimental groups. Pulmonary function was assessed weekly by whole-body plethysmography, determining the enhanced pause (Penh) at baseline, after treatment, and after CS/sham exposure. Lung changes were evaluated by morphometry and immunohistochemistry. CS exposure increased Penh in all conditions. CS-exposed animals treated with aclidinium showed lower baseline Penh than untreated animals (P = 0.02). CS induced thickening of all bronchial wall layers, airspace enlargement, and inflammatory cell infiltrate in airways and septa. Treatment with aclidinium abrogated the CS-induced smooth muscle enlargement in small airways (P = 0.001), and tended to reduce airspace enlargement (P = 0.054). Aclidinium also attenuated CS-induced neutrophilia in alveolar septa (P = 0.04). We conclude that, in guinea pigs chronically exposed to CS, aclidinium has an antiremodeling effect on small airways, which is associated with improved respiratory function, and attenuates neutrophilic infiltration in alveolar septa. These results indicate that, in COPD, aclidinium may exert beneficial effects on lung structure in addition to its bronchodilator action.

Topics: Airway Remodeling; Animals; Disease Models, Animal; Guinea Pigs; Inflammation; Lung; Male; Muscarinic Antagonists; Nicotiana; Pulmonary Disease, Chronic Obstructive; Smoke; Tropanes

Topics: Administration, Inhalation; Drug Chronotherapy; Germany; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

Topics: Administration, Inhalation; Administration, Oral; Contraindications; Drug Interactions; Humans; Pulmonary Disease, Chronic Obstructive; Tropanes

Long-acting muscarinic receptor antagonists (LAMAs) and long-acting β2-adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles). We analyzed the potential synergistic interaction between the compounds when administered in combination by using Bliss independence (BI) theory. Both aclidinium bromide and formoterol fumarate completely relaxed segmental bronchi pre-contracted with acetylcholine (Emax: 97.5±2.6% and 96.4±1.1%; pEC50 8.5±0.1 and 8.8±0.1; respectively). Formoterol fumarate, but not aclidinium bromide, abolished the contraction induced by acetylcholine in bronchioles (Emax: 68.1±4.5% and 99.0±5.6%; pEC50 7.9±0.3 and 8.4±0.3; respectively). The BI analysis indicated synergistic interaction at low concentrations in segmental bronchi (+18.4±2.7%; P<0.05 versus expected effect) and from low to high concentrations in bronchioles (+19.7±0.9%; P<0.05 versus expected effect). Low concentrations of both drugs produced a synergistic relaxant interaction on isolated bronchi stimulated with EFS that was sustained for 6h post-treatment (+55.1±9.4%; P<0.05 versus expected effect). These results suggest that combining aclidinium bromide plus formoterol fumarate provides synergistic benefit on ASM relaxation of both medium and small human airways, which may have major implications for the use of this combination in the clinic.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchi; Bronchioles; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Synergism; Electric Stimulation; Ethanolamines; Female; Formoterol Fumarate; Humans; In Vitro Techniques; Male; Middle Aged; Models, Biological; Muscarinic Antagonists; Muscle Relaxation; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Tropanes

A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.

Topics: Administration, Inhalation; Animals; Bronchoconstriction; Cycloheptanes; Disease Models, Animal; Guinea Pigs; Humans; Molecular Structure; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic

Combining a long-acting β(2)-agonist (LABA) and a long-acting antimuscarinic agent (LAMA) is potentially a good pharmacological approach to improve clinical results in stable moderate chronic obstructive pulmonary disease (COPD) patients when symptoms are not adequately controlled with tiotropium monotherapy. Consequently, there is a strong interest in developing a LABA/LAMA fixed-dose combination therapy in an attempt to simplify the treatment.. An aclidinium bromide/formoterol fumarate fixed-dose combination is under development. The few clinical data at our disposal suggest that the addition of formoterol fumarate to aclidinium bromide results in greater bronchodilation than formoterol fumarate or aclidinium bromide alone. However, a large Phase III program is involving a huge number of patients with moderate-to-severe COPD and consists of large long-term (from 24 to 52 weeks) pivotal clinical trials that have been designed to fulfil both European Medicines Agency (EMA) and Food and Drug Administration (FDA) requirements and are evaluating the efficacy and safety of this fixed-dose combination.. Studies assessing the impact of aclidinium bromide/formoterol fumarate fixed-dose combination on COPD exacerbations, exercise capacity and hospitalisations are clearly needed to better detect its potential effects of disease modification in COPD. Moreover, it seems pragmatic to proceed with its introduction in the market at a highly competitive price.

Topics: Bronchodilator Agents; Drug Combinations; Drug Design; Ethanolamines; Formoterol Fumarate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tropanes

Chronic obstructive pulmonary disease (COPD) affects around 64 million people worldwide and is the fourth leading cause of death.(1) In Europe, COPD is thought to be responsible for the deaths of 200,000 to 300,000 people each year and its economic burden estimated to be EUR102 billion/year.(1) In 2011, over 1.5 million people (3.6% of the population ≥ 16 years) in England had COPD, which included 720,000 people aged over 65.(2) Drug management of COPD includes treatments to relieve respiratory symptoms, and prevent or manage acute exacerbations. Short-acting inhaled bronchodilators (either a beta2 agonist [SABA] or muscarinic antagonist [SAMA]) are used as initial empirical treatment to relieve breathlessness and reduce exercise limitation. Long-acting bronchodilators with or without an inhaled corticosteroid (ICS) are added for people who remain breathless or have exacerbations.(3) Aclidinium bromide powder for inhalation (Eklira Genuair-Almirall) is a long-acting muscarinic antagonist (LAMA), licensed to be used twice a day as a maintenance bronchodilator to relieve symptoms in adults with COPD.(4) In this article, we consider the evidence for aclidinium and how its use fits with current management strategies for COPD.

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Humans; Middle Aged; Muscarinic Antagonists; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Treatment Outcome; Tropanes; United Kingdom

Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently in registration phase for the treatment of chronic obstructive pulmonary disease. Since urinary difficulty and retention have been reported for anticholinergic agents such as tiotropium and ipratropium, it is important to examine the preclinical urinary and renal safety profile of aclidinium.. The effect of aclidinium on urine and electrolyte excretion, renal function and voiding cystometry was analysed in conscious water-loaded Wistar rats (10-1000 μg/kg, s.c.), anaesthetised Beagle dogs (1000 μg/kg, i.v.) and anaesthetised guinea pigs (3-100μg/kg, intratracheally), respectively. Aclidinium plasma levels were determined in an independent study. Active comparators were tiotropium (all studies) and ipratropium (cystometry only).. Aclidinium 1000 μg/kg had no effect on urine excretion in rats, in contrast to tiotropium 100 μg/kg which significantly decreased this parameter (p<0.05). Aclidinium 1000 μg/kg also had no effect on renal function in Beagle dogs. In guinea pigs, aclidinium 3-100 μg/kg had no effect on urinary bladder function, whereas tiotropium and ipratropium 100 μg/kg decreased the peak micturition pressure (p<0.05), increased the volume of urine retained in the bladder (p<0.01) and showed a trend to decrease the volume of urine excreted.. Aclidinium had no significant effect on urinary and renal function in the animal models studied. These results, together with the rapid plasma clearance of aclidinium reported previously, suggest a lower propensity to induce urinary retention in humans than tiotropium and ipratropium.

Topics: Animals; Dogs; Female; Guinea Pigs; Kidney; Kidney Function Tests; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Tropanes

Topics: Administration, Inhalation; Administration, Oral; Cholinergic Antagonists; Drug Approval; Humans; Pulmonary Disease, Chronic Obstructive; Tropanes

Aclidinium, an inhaled, long-acting antimuscarinic agent, has been developed as a twice-daily maintenance treatment for chronic obstructive pulmonary disease (COPD). Treatment with the approved dosage of aclidinium (400 μg twice daily) statistically significantly improved bronchodilation, disease-specific health status, dyspnoea, night-time COPD symptoms and use of rescue medication compared with placebo in pivotal studies of 12 (ACCORD COPD I) or 24 (ATTAIN) weeks duration in patients with moderate to severe COPD. The improvements in bronchodilation, health status and dyspnoea were clinically meaningful compared with placebo after 24 weeks of treatment in ATTAIN; generally similar results were seen after 12 weeks of treatment in both trials. Aclidinium also statistically significantly reduced the incidence of COPD exacerbations compared with placebo in these studies (albeit neither trial was designed to assess exacerbation frequency). Inhaled aclidinium has a low systemic bioavailability; the approved dosage was generally well tolerated in clinical trials of up to 52 weeks duration. Aclidinium had an adverse event profile that was similar to that of placebo and characterized by low incidences of major adverse cardiovascular events and potential anticholinergic adverse events.

Topics: Biological Availability; Bronchodilator Agents; Dyspnea; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tropanes

The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.

Topics: Blood Proteins; Drug Evaluation, Preclinical; Humans; Muscarinic Antagonists; Piperidines; Protein Binding; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Receptor, Muscarinic M3; Structure-Activity Relationship

Mucus hypersecretion and mucin MUC5AC overexpression are pathological features of chronic obstructive pulmonary disease (COPD). This study examines the inhibitory effect of aclidinium, a new long-acting muscarinic antagonist, on MUC5AC expression in human airway epithelial cells. MUC5AC mRNA (RT-PCR) and protein expression (ELISA and immunohistochemistry) were studied in human bronchial tissue and differentiated human airway epithelial cells activated with carbachol (100 μM) or cigarette smoke extract in the absence or presence of aclidinium. Carbachol increased MUC5AC mRNA and protein expression in human bronchus and cultured epithelial cells. Aclidinium inhibited the carbachol-induced MUC5AC mRNA and protein expression with potency (half maximal inhibitory concentration) ~1 nM in human bronchus and cultured airway epithelial cells. AG1478, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, inhibited carbachol-induced MUC5AC responses, indicating EGFR transactivation. Aclidinium inhibited carbachol-induced phospho-EGFR and phospho-p44/42 MAPK expression. In cultured airway epithelial cells transfected with small interfering (si)RNA against muscarinic receptor subtypes, siRNA-M3 but not siRNA-M2 blocked carbachol-induced MUC5AC expression. Cigarette smoke-induced MUC5AC upregulation in cultured airway epithelial cells was suppressed by aclidinium. In conclusion, aclidinium decreases carbachol and tobacco smoke-induced MUC5AC overexpression in human airway epithelial cells. This effect may contribute to the clinical efficacy of aclidinium in mucus hypersecretory diseases including COPD.

Topics: Carbachol; Cells, Cultured; Epithelial Cells; ErbB Receptors; Humans; Mitogen-Activated Protein Kinases; Mucin 5AC; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory System; RNA, Small Interfering; Smoking; Tropanes

Airway hyperresponsiveness and inflammation characterize the airways of individuals with asthma and chronic obstructive pulmonary disease (COPD). Hence, therapeutic approaches that attenuate such manifestations may offer promise in the management of these diseases. In the present study, we investigated whether a novel long-acting cholinergic antagonist, aclidinium bromide, modulates airway function and leukocyte trafficking in an Aspergillus fumigatus (Af)-induced murine model of asthma. Nebulized aclidinium (1 mg/ml) administration completely abrogated increases in methacholine-induced lung resistance in Af-exposed mice. Parallel assessment of dynamic compliance showed that aclidinium also completely restores methacholine-mediated decreases in naïve and Af-exposed mice. As evidenced by differential cell counts within bronchoalveolar lavage fluid, aclidinium also diminished (51±4%) Af-induced airway eosinophil numbers with no significant change in other immune cell types. Further assessment of cytokine and total protein levels in bronchoalveolar lavage fluid showed that aclidinium had little effect on IL-4 or IL-6 levels in either Af-exposed or naïve mice but markedly decreased total protein levels in bronchoalveolar lavage fluid. These data suggest that aclidinium, a selective muscarinic antagonist, not only acts as a bronchodilator but could also act as an anti-inflammatory agent with potential clinical benefits in the treatment of COPD and asthma.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens, Fungal; Asthma; Bronchitis; Bronchoalveolar Lavage Fluid; Cell Count; Cholinergic Antagonists; Cytokines; Female; Inflammation; Leukocytes; Mice; Mice, Inbred BALB C; Pulmonary Disease, Chronic Obstructive; Pulmonary Eosinophilia; Respiratory Hypersensitivity; Respiratory System; Tropanes

The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.

Topics: Administration, Inhalation; Animals; Bronchial Spasm; CHO Cells; Cricetinae; Cricetulus; Drug Stability; Esters; Guinea Pigs; Humans; Male; Mice; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quaternary Ammonium Compounds; Quinuclidines; Radioligand Assay; Receptor, Muscarinic M3; Stereoisomerism; Structure-Activity Relationship; Tropanes