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Therapeutic Advances in Respiratory... 2019Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) fixed-dose combination (FDC) is an established treatment strategy for... (Comparative Study)
Comparative Study Meta-Analysis
Systematic review and network meta-analysis of the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler in comparison with other long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combinations in COPD.
BACKGROUND
Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) fixed-dose combination (FDC) is an established treatment strategy for chronic obstructive pulmonary disease (COPD). The relative efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 18/9.6 μg) in patients with moderate-to-very severe COPD, compared with other licensed LAMA/LABA FDCs, was investigated using an integrated Bayesian network meta-analysis (NMA).
METHODS
A systematic literature review and subsequent screening process identified randomized controlled trials of ⩾10 weeks' duration that enrolled patients aged ⩾40 years with moderate-to-very severe COPD and included at least one LAMA/LABA FDC or open LAMA + LABA treatment arm. NMAs were conducted for outcomes including change from baseline in forced expiratory volume in 1 s (FEV), St George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI) parameters, annualized rate of exacerbations, use of rescue medication, adverse events, and all-cause withdrawals. Meta-regression and sensitivity analyses accounted for heterogeneity across studies.
RESULTS
In total, 29 studies including 34,617 patients contributed to the NMA for efficacy or safety outcomes at week 24 or exacerbations. For all LAMA/LABA FDCs with data available, significantly greater improvements in FEV [trough, peak, and area under the curve (AUC)], SGRQ total score and TDI focal score at week 24, and annualized rate of moderate-to-severe exacerbations, were observed placebo. Where indirect comparisons were possible, differences between GFF MDI and other LAMA/LABA FDCs were small relative to established margins of clinical relevance, and not statistically significant. The safety and tolerability profile of GFF MDI was consistent with other LAMA/LABA FDCs and placebo. The results of the meta-regression were generally similar to the base case.
CONCLUSIONS
GFF MDI demonstrated comparable efficacy and safety outcomes to other LAMA/LABA FDCs. Personalization of treatment choice within the class on the basis of other factors such as patient preference may be appropriate.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Metered Dose Inhalers; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic
PubMed: 31868101
DOI: 10.1177/1753466619894502 -
Chronic Respiratory Disease 2023The rationale for additional treatment with short-acting bronchodilators combined with long-acting bronchodilators for patients with chronic obstructive pulmonary... (Meta-Analysis)
Meta-Analysis
The efficacy and safety of additional treatment with short-acting muscarinic antagonist combined with long-acting beta-2 agonist in stable patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.
BACKGROUND
The rationale for additional treatment with short-acting bronchodilators combined with long-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is not adequately studied.
METHODS
We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of a short-acting muscarinic antagonist (SAMA) therapy combined with a long-acting beta-2 agonist (LABA) in patients with stable COPD. Pulmonary function, dyspnea, health-related quality of life, exercise tolerance, physical activity, exacerbations of COPD, and adverse events during regular use were set as outcomes of interest.
RESULTS
We included five controlled trials including two sets of publicly available online data without article publications for the meta-analysis. Additional use of SAMA plus LABA showed a significant improvement in the peak response in FEV (mean difference (MD) 98.70 mL, < .00001), transitional dyspnea index score (MD .85, = .02), and St George's Respiratory Questionnaire score (MD -2.00, = .008) compared to LABA treatment. There was no significant difference in the risk of exacerbation of COPD ( = .20) and only a slight trend of increased severe adverse events (OR: 2.16, = .08) and cardiovascular events (OR: 2.38, = .06).
CONCLUSION
Additional treatment with SAMA combined with LABA could be a feasible choice due to its efficacy and safety.
Topics: Humans; Muscarinic Antagonists; Bronchodilator Agents; Adrenergic beta-2 Receptor Agonists; Quality of Life; Pulmonary Disease, Chronic Obstructive; Administration, Inhalation; Dyspnea
PubMed: 36967224
DOI: 10.1177/14799731231166008 -
The Annals of Pharmacotherapy Mar 2019To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS)... (Review)
Review
OBJECTIVE
To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS) nebulizer, approved for maintenance treatment of chronic obstructive pulmonary disease (COPD).
DATA SOURCES
A PubMed search was conducted (January 2000 to July 2018) using the following terms/phrases: nebulized glycopyrrolate, inhalation devices in COPD, long-acting muscarinic antagonists COPD, and COPD survey. Retrieved articles were reviewed to identify additional references.
STUDY SELECTION AND DATA EXTRACTION
Primary and review articles on GLY/eFlow CS and other treatment options for patients with COPD were selected.
DATA SYNTHESIS
Guidelines recommend the use of LAMAs, alone or in combination with long-acting β-agonists, as maintenance therapy for the majority of patients with COPD. With the range of different devices and bronchodilators now available, treatment can be tailored based on individual needs. The eFlow CS nebulizer delivers GLY rapidly over a 2- to 3-minute period and provides bronchodilation within 30 minutes, lasting 12 hours. Phase 2 dose-finding and phase 3 studies demonstrated sustained statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with GLY/eFlow CS. Relevance to Patient Care and Clinical Practice: GLY/eFlow CS provides a novel, portable, efficient, and rapid drug delivery system.
CONCLUSIONS
The recently approved GLY/eFlow CS drug-device combination provides a viable treatment option for patients with COPD, particularly those with conditions that may impair proper use of traditional handheld inhalers.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Delivery Systems; Female; Glycopyrrolate; Humans; Male; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Treatment Outcome
PubMed: 30175596
DOI: 10.1177/1060028018798753 -
Pulmonary Pharmacology & Therapeutics Feb 2018Revefenacin (TD-4208) is a potent, lung-selective, long-acting muscarinic antagonist currently in development as a once-daily nebulized therapy for chronic obstructive... (Comparative Study)
Comparative Study Randomized Controlled Trial
Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies.
BACKGROUND
Revefenacin (TD-4208) is a potent, lung-selective, long-acting muscarinic antagonist currently in development as a once-daily nebulized therapy for chronic obstructive pulmonary disease (COPD). We evaluated the pharmacodynamics (bronchodilator activity), pharmacokinetics (PK) and safety of single- and multiple-dose administrations of revefenacin in two clinical trials (Study 0059 and Study 0091) in patients with moderate to severe COPD.
METHODS
In Study 0059, 32 patients were randomized to receive a single dose of revefenacin (350 or 700 μg), active control ipratropium (500 μg) or placebo inhalation solution administered via standard jet nebulizer in a double-blind, crossover fashion. In Study 0091, 59 patients were randomized to receive once-daily inhalations of revefenacin (22, 44, 88, 175, 350 or 700 μg) or placebo for 7 days in a double-blind, incomplete block, five-way crossover design. The primary efficacy endpoint was change from baseline in peak (0-6 h) forced expiratory volume in 1 s (FEV) in Study 0059, and trough FEV after the final dose (Day 7) in Study 0091. In both studies, secondary endpoints included area under the FEV-time curve (FEV AUC) values from time 12-24 h post dose and FEV AUC values from time zero to 24 h post dose.
RESULTS
Revefenacin demonstrated a rapid onset and sustained duration of bronchodilator action in both studies. In Study 0059, mean peak FEV was significantly higher (p < 0.001) for revefenacin and ipratropium compared to placebo, with differences of 176.8 mL for 350 μg revefenacin, 162.2 mL for 700 μg revefenacin and 190.6 mL for ipratropium. In Study 0091, mean trough FEV on Day 7 was significantly higher (p < 0.006) for all revefenacin doses compared to placebo, with differences ranging from 53.5 mL (22 μg dose) to 114.2 mL (175 μg dose). The results for the other spirometry endpoints were consistent with the primary endpoint for each study, demonstrating that the bronchodilator effect of revefenacin lasted more than 24 h following nebulized administration. Revefenacin was rapidly absorbed and extensively metabolized, followed by a slow apparent terminal elimination and minimal accumulation with repeated dosing. In both studies, adverse events were generally mild and occurred with similar frequencies in all groups, with no indication of significant systemic anti-muscarinic activity at any dose.
CONCLUSIONS
Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure.
Topics: Administration, Inhalation; Aged; Benzamides; Bronchodilator Agents; Carbamates; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Spirometry; Time Factors
PubMed: 28987804
DOI: 10.1016/j.pupt.2017.10.003 -
International Journal of Environmental... Jun 2018Ambient particulate matter (PM) can increase airway inflammation and induce bronchoconstriction in asthma. This study aimed to investigate the effect of tiotropium... (Comparative Study)
Comparative Study
Ambient particulate matter (PM) can increase airway inflammation and induce bronchoconstriction in asthma. This study aimed to investigate the effect of tiotropium bromide, a long-acting muscarinic antagonist, on airway inflammation and bronchoconstriction induced by ambient PM in a mouse model of asthma. We compared the effect of tiotropium bromide to that of fluticasone propionate and formoterol fumarate. BALB/c mice were sensitized to ovalbumin (OVA) via the airways and then administered tiotropium bromide, fluticasone propionate, or formoterol fumarate. Mice were also sensitized to ambient PM via intranasal instillation. Differential leukocyte counts and the concentrations of interferon (IFN)-γ, interleukin (IL)-5, IL-6, IL-13, and keratinocyte-derived chemokine (KC/CXCL1) were measured in bronchoalveolar lavage fluid (BALF). Diacron-reactive oxygen metabolites (dROMs) were measured in the serum. Airway resistance and airway inflammation were evaluated in lung tissue 24 h after the OVA challenge. Ambient PM markedly increased neutrophilic airway inflammation in mice with OVA-induced asthma. Tiotropium bromide improved bronchoconstriction, and reduced neutrophil numbers, decreased the concentrations of IL-5, IL-6, IL-13, and KC/CXCL1 in BALF. However, tiotropium bromide did not decrease the levels of dROMs increased by ambient PM. Though eosinophilic airway inflammation was reduced with fluticasone propionate, neutrophilic airway inflammation was unaffected. Bronchoconstriction was improved with formoterol fumarate, but not with fluticasone propionate. In conclusion, tiotropium bromide reduced bronchoconstriction, subsequently leading to reduced neutrophilic airway inflammation induced by ambient PM.
Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cytokines; Disease Models, Animal; Inflammation; Leukocyte Count; Male; Mice; Mice, Inbred BALB C; Muscarinic Antagonists; Particulate Matter; Reactive Oxygen Species
PubMed: 29882826
DOI: 10.3390/ijerph15061189 -
The Journal of Allergy and Clinical... Jul 2021Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine...
BACKGROUND
Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine formulations of the inhaled corticosteroid (ICS) beclomethasone dipropionate (BDP), long-acting β-agonist formoterol fumarate (FF), and long-acting muscarinic antagonist glycopyrronium (G) is in development for asthma.
OBJECTIVE
We sought to evaluate whether calendar season impacted the relative effect of BDP/FF/G versus BDP/FF on moderate and severe asthma exacerbations.
METHODS
TRIMARAN and TRIGGER were double-blind 52-week studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma (Asthma Control Questionnaire-7 score ≥1.5), prebronchodilator FEV less than 80% predicted, history of 1 or more asthma exacerbation, who had been receiving ICS/long-acting β-agonist for at least 4 weeks before entry. Moderate and severe asthma exacerbations were captured throughout each study. In these post hoc analyses, the annual moderate and severe exacerbation rate was calculated for each month, with rate ratios determined from events grouped by season.
RESULTS
In patients who received BDP/FF alone, there was a marked seasonal effect on the occurrence of asthma exacerbations, with the rate highest in the winter months. However, the addition of the long-acting muscarinic antagonist component to BDP/FF reduced this seasonal variation, especially during the winter, such that the relative effect of BDP/FF/G versus BDP/FF was greatest in the winter (significant 20.3% reduction [P = .0008]). Reductions in the other seasons ranged between 8.6% and 12.0%.
CONCLUSIONS
These post hoc analyses indicate that inhaled triple therapy with extrafine BDP/FF/G reduces seasonal peaks in moderate and severe exacerbations, and confirm the overall utility of adding long-acting muscarinic antagonist to ICS/long-acting β-agonist in the management of asthma.
Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bronchodilator Agents; Double-Blind Method; Female; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Young Adult
PubMed: 33485959
DOI: 10.1016/j.jaci.2021.01.007 -
Annals of Allergy, Asthma & Immunology... Oct 2015Asthma is a chronic inflammatory disorder of the airways with increasing worldwide prevalence. Despite treatment according to guidelines, a considerable proportion of... (Review)
Review
OBJECTIVE
Asthma is a chronic inflammatory disorder of the airways with increasing worldwide prevalence. Despite treatment according to guidelines, a considerable proportion of patients with asthma remain symptomatic. Different potential therapeutic options for the treatment of these patients are currently in development and undergoing clinical trials, and it is important to regularly review their status.
DATA SOURCES
A search of ClinicalTrials.gov was performed and supported by a PubMed literature search and restricted to the previous 10 years to ensure currency of data. The results were manually filtered to identify relevant articles.
STUDY SELECTIONS
Emerging therapies that are currently in phase 2 and 3 development include anti-interleukin agents (benralizumab, reslizumab, dupilumab, brodalumab, lebrikizumab, and mepolizumab), a chemoattractant receptor-homologous molecule expressed on a T-helper type 2 lymphocyte antagonist (OC000459), a phosphodiesterase-4 inhibitor (roflumilast), and long-acting muscarinic antagonists (glycopyrronium bromide, umeclidinium bromide, and tiotropium bromide).
RESULTS
The clinical trial program of the long-acting muscarinic antagonist tiotropium is currently the most advanced, with data available from different phase 2 and 3 studies. Results demonstrate that it is an efficacious add-on to at least inhaled corticosteroid maintenance therapy across severities of symptomatic asthma.
CONCLUSION
The results of ongoing and future studies will help to determine whether these emerging therapeutic options will help address the unmet need for improvement in asthma management.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Asthma; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Indoleacetic Acids; Interleukins; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Quinolines; Tiotropium Bromide
PubMed: 26254973
DOI: 10.1016/j.anai.2015.07.011 -
Scientific Reports Feb 2014Alpha-adrenoceptor antagonists (alpha-blockers) are widely prescribed to treat lower urinary tract symptoms (LUTS) in men but fail to ameliorate LUTS sufficiently,... (Comparative Study)
Comparative Study Meta-Analysis Review
Alpha-adrenoceptor antagonists (alpha-blockers) are widely prescribed to treat lower urinary tract symptoms (LUTS) in men but fail to ameliorate LUTS sufficiently, especially the storage symptoms related to frequency, urgency and nocturia. We performed a meta-analysis of randomised controlled trials (RCTs) comparing an alpha-blocker plus muscarinic antagonist with an alpha-blocker alone in male LUTS patients who were treated with alpha-blocker prior to randomisation. The review contained six randomised controlled trials (RCTs) that included a total of 2,208 male patients who were randomised to receive alpha-blocker plus muscarinic antagonist or alpha-blocker alone. The add-on group experienced significantly greater improvement in both total IPSS (International Prostate Symptom Score) and storage IPSS. Adverse events (AEs) were commonly experienced by both groups (41.6 vs. 33.3%) though they were not severe. Our meta-analysis indicated that muscarinic antagonists as add-on therapy alleviate LUTS, especially storage symptoms. The add-on therapy demonstrated safety and tolerability comparable with alpha-blocker monotherapy in male with LUTS.
Topics: Adrenergic alpha-Antagonists; Aged; Aged, 80 and over; Humans; Lower Urinary Tract Symptoms; Male; Middle Aged; Muscarinic Antagonists
PubMed: 24492830
DOI: 10.1038/srep03948 -
International Journal of Chronic... 2015Three long-acting muscarinic antagonists (LAMAs) are now available in Europe, providing clinicians and patients with a choice of interventions, which is important in... (Review)
Review
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
PubMed: 25848244
DOI: 10.2147/COPD.S76520 -
Therapeutic Advances in Respiratory... Jun 2011Bronchodilation with a long-acting muscarinic antagonist (LAMA) or long-acting β(2)-agonist is central to the management of chronic obstructive pulmonary disease... (Review)
Review
Bronchodilation with a long-acting muscarinic antagonist (LAMA) or long-acting β(2)-agonist is central to the management of chronic obstructive pulmonary disease (COPD). Tiotropium, the first LAMA available for use in COPD, has been shown to be an effective bronchodilator and is generally safe and well tolerated. However, tiotropium has limitations that include a high incidence of dry mouth, slow onset of action and, in some studies, a part of the patient population did not achieve clinically significant bronchodilation. It also remains unclear whether tiotropium reduces progressive deterioration of lung function in patients with COPD. An ideal LAMA would provide clinically meaningful bronchodilation, deliver symptom relief, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations and reduce mortality risk. A 24-h duration of action, rapid onset of action and a good safety and tolerability profile are also desirable. The once-daily LAMA, NVA237 (glycopyrronium bromide), may meet some of these characteristics. NVA237 has high selectivity for the muscarinic type-3 (M(3)) receptor which might potentially result in a higher therapeutic index than tiotropium, which is less selective for M(3). Phase II studies showed that NVA237 once daily provides clinically significant 24-h bronchodilation with a rapid onset of action and a favourable safety and tolerability profile. Phase III studies are ongoing that will assess the long-term safety and efficacy of NVA237.
Topics: Bronchodilator Agents; Delayed-Action Preparations; Glycopyrrolate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide
PubMed: 21511677
DOI: 10.1177/1753465811406001