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Background: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β 2 -agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking., Methods: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only., Results: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group., Conclusions: Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.)., (Copyright © 2020 Massachusetts Medical Society.)

Background/objectives: Glycopyrronium tosylate (GT) cloth, 2.4% is a topical anticholinergic approved in the United States for primary axillary hyperhidrosis in patients ≥9 years. This post hoc analysis evaluated long-term response (efficacy and safety) in pediatric patients (≥9 to ≤16 years) to GT in the 44-week, open-label extension (NCT02553798) of two, phase 3, double-blind, vehicle-controlled, 4-week trials (NCT02530281, NCT02530294)., Methods: In the double-blind trials, patients ≥9 years with primary axillary hyperhidrosis were randomized 2:1 to once-daily GT:vehicle. Those who completed the study could receive open-label GT for up to an additional 44 weeks. Safety assessments included treatment-emergent adverse events (TEAEs) and local skin reactions (LSRs). Descriptive efficacy assessments included gravimetrically measured sweat production, Hyperhidrosis Disease Severity Scale response (≥2-grade improvement), and Children's Dermatology Life Quality Index., Results: Of 43 pediatric patients completing either double-blind trial, 38 (88.4%) entered the open-label extension (age, years: 9 [n = 1], 12 [n = 2], 13 [n = 7], 14 and 15 [n = 9 each], 16 [n = 10]). The safety profile observed was similar to the double-blind trials. Most TEAEs (>95%) were mild/moderate, related to anticholinergic activity, and infrequently led to discontinuation (n = 1/38 [2.6%]). No pediatric patients experienced a serious TEAE. Most anticholinergic TEAEs did not require a dose modification and resolved within 7 days. Approximately, one-third of patients (n = 13/38 [34.2%]) had LSRs; most were mild/moderate in severity. Improvements in efficacy measures were maintained from the double-blind trials., Conclusions: Long-term, once-daily GT for up to 48 weeks (4-week double-blind plus 44 week open label) provides a noninvasive, well-tolerated treatment option for pediatric patients with primary axillary hyperhidrosis., (© 2020 The Authors. Pediatric Dermatology published by Wiley Periodicals, Inc.)

Background: The anticholinesterase neostigmine and the muscarinic inhibitor glycopyrrolate are frequently coadministered for the reversal of neuromuscular blockade. This practice can precipitate severe bradycardia or tachycardia, but whether it affects the incidence of cardiovascular complications remains unclear. We hypothesized that anticholinesterase reversal with neostigmine and glycopyrrolate versus no anticholinesterase reversal increases the risk of postoperative cardiovascular complications among adult patients undergoing noncardiac surgery with general anesthesia., Methods: We conducted a prespecified retrospective analysis of hospital registry data from a major health care network for patients undergoing surgery with general anesthesia from January 2007 to December 2015. The primary outcome was a composite of cardiac dysrhythmia, acute heart failure, transient ischemic attack, ischemic stroke, and acute myocardial infarction within 30 days after surgery. We performed sensitivity analyses in subgroups and propensity score adjustment and explored the association between exposure and outcome in subgroups of patients with high risk of cardiovascular complications., Results: Of the 98,147 cases receiving neuromuscular blockade, 73,181 (74.6%) received neostigmine and glycopyrrolate, while 24,966 (25.4%) did not. A total of 5612 patients (7.7%) in the anticholinesterase reversal group and 1651 (6.6%) in the control group (P < .001) experienced the primary outcome. After adjustment for clinical covariates, neostigmine and glycopyrrolate exposure was significantly associated in a dose-dependent fashion (P for trend <.001, respectively) with tachycardia (adjusted odds ratio = 2.1 [95% CI, 1.97-2.23]; P < .001) and bradycardia (adjusted odds ratio = 2.84 [95% CI, 2.49-3.24]; P < .001) but not with postoperative cardiovascular complications (adjusted odds ratio = 1.03 [95% CI, 0.97-1.1]; P = .33). We identified a significant effect modification of anticholinesterase reversal by high age, high-risk surgery, and history of atrial fibrillation (P for interaction = .002, .001, and .02, respectively). By using linear combinations of main effect and exposure-risk interaction terms, we detected significant associations between anticholinesterase reversal and cardiovascular complications toward a higher vulnerability in these patient subgroups., Conclusions: Neuromuscular blockade reversal with neostigmine and glycopyrrolate was associated with an increased incidence of intraoperative tachycardia and bradycardia but not with 30-day postoperative cardiovascular complications. Exploratory analyses suggest that a high postoperative cardiovascular complication risk profile may modify the effects of anticholinesterase reversal toward clinical relevance.

Purpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β 2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone., Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization., Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in ( p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods., Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO., Competing Interests: The authors declare that they have no competing interests in this work., (© 2020 Ishiura et al.)

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD. We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD., Materials and Methods: PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458). Patients received 24 weeks' treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI twice daily. GOLD category A patients were identified based on a COPD Assessment Test score of <10 and exacerbation history in the previous year (none/one not requiring hospitalization). Endpoints evaluated were change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV 1 ), peak change from baseline in FEV 1 within 2 hrs post-dose, and adverse events (AEs)., Results: The pooled intent-to-treat population comprised 729 GOLD category A patients. GFF MDI significantly improved morning pre-dose trough FEV 1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all p ≤0.0053), and peak FEV 1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all p <0.0001). Improvements over 24 weeks were comparable to at Week 24. The AE profile of GFF MDI in GOLD category A patients was similar to monocomponents and placebo MDI., Conclusion: GFF MDI significantly improved lung function versus monocomponents and placebo MDI in GOLD category A patients with moderate-to-very severe COPD, with no unexpected safety findings., Competing Interests: FJM reports personal fees and non-financial support from American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, Chiesi, Concert, Continuing Education, Gala, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, National Association for Continuing Education, Novartis, Pearl – a member of the AstraZeneca Group, PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Roche, Sunovion, and Theravance; non-financial support from ProterixBio; personal fees from American Thoracic Society, Columbia University, Haymarket Communications, Integritas, inThought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Teva, Unity, UpToDate, WebMD/MedScape, and Western Connecticut Health Network; and grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and National Institutes of Health. KFR reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Pharmaceuticals, InterMune, Novartis, Sanofi, and Teva; and grants from the Ministry of Education and Science, Germany. BJL is one of a number of co-investigators on an AstraZeneca-sponsored grant received by the University of Dundee to support genomic studies in COPD. He has also received speaker fees from AstraZeneca; payment for consulting and speaking from Boehringer Ingelheim and Chiesi; grant support from Boehringer Ingelheim, Chiesi, and Janssen; advisory board and speaker fees from Teva; and consulting fees from Sandoz, Cipla, Dr Reddys, and Lupin. MJ, UJM, and CR are employees of AstraZeneca and hold stock and/or stock options in the company. The authors report no other conflicts of interest in this work., (© 2020 Martinez et al.)

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting β 2 -agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4., Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study., Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all P≤ 0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group., Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China., Competing Interests: RC is an advisory committee member and speaker for AstraZeneca. NZ has received consultancy and lecture fees from Boehringer Ingelheim and Novartis and was on the advisory board of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) committee. XM and ZQ are speakers for AstraZeneca. JH and PNA are employees of AstraZeneca Shanghai, People's Republic of China. AM, SS, UJM, and CR are employees of AstraZeneca, with stock options. The authors report no other conflicts of interest in this work., (© 2020 Chen et al.)

Background: Functional respiratory imaging (FRI) is a quantitative postprocessing imaging technique used to assess changes in the respiratory system. Using FRI, we characterized the effects of the long-acting muscarinic antagonist (LAMA), glycopyrrolate metered dose inhaler (GP MDI), and the long-acting β 2 -agonist (LABA), formoterol fumarate metered dose inhaler (FF MDI), on airway volume and resistance in patients with moderate-to-severe chronic obstructive pulmonary disease., Methods: Patients in this phase IIIb, randomized, double-blind crossover study received twice-daily GP MDI (18 μg) and FF MDI (9.6 μg). Primary endpoints were specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and specific image-based airway resistance (siRaw), measured using FRI. Secondary and other endpoints included additional FRI, spirometry, and body plethysmography parameters. Postdose efficacy assessments were performed within 60-150 min of dosing on day 15., Results: A total of 23 patients were randomized and 19 completed both treatment periods. GP MDI and FF MDI both achieved significant improvements from baseline to day 15 in siVaw [11% ( p  = 0.0187) and 23% ( p  < 0.0001) increases, respectively] and siRaw [25% ( p  = 0.0219) and 44% ( p  < 0.0001) reductions, respectively]. Although, on average, improvements were larger for FF MDI than GP MDI, some individuals displayed greater responses with each of the two treatments. These within-patient differences increased with airway generation number. Spirometry and body plethysmography endpoints showed significant improvements from baseline in inspiratory capacity for both treatments, and numeric improvements for other endpoints., Conclusion: Both GP MDI and FF MDI significantly improved siRaw and siVaw at day 15 versus baseline. FRI endpoints demonstrated increased sensitivity relative to spirometry and body plethysmography in detecting differences between treatments in a small number of patients. Intra-patient differences in treatment response between the LAMA and the LABA provide further support for the benefit of dual bronchodilator therapies., Clinicaltrials.gov Registration Number: NCT02937584 The reviews of this paper are available via the supplemental material section.

Background: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea., Methods: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements., Results: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean -1.00, 95% confidence interval (CI) -1.49 to -0.52] but not with tiotropium alone (mean -0.36, 95% CI -0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of -0.64, 95% CI -1.11 to -0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI -0.44 to 0.61)., Conclusion: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation. The reviews of this paper are available via the supplemental material section.

Background: Glycopyrronium tosylate is a topical anticholinergic approved in the USA for primary axillary hyperhidrosis in patients aged ≥ 9 years (Qbrexza™ [glycopyrronium] cloth, 2.4%)., Objective: This 44-week open-label extension study assessed glycopyrronium tosylate safety and descriptive efficacy in patients completing one of two, phase III, double-blind, vehicle-controlled, 4-week trials (NCT02530281; NCT02530294)., Methods: Patients aged ≥ 9 years with primary axillary hyperhidrosis were randomized 2:1 (glycopyrronium tosylate: vehicle, once daily) in the double-blind trials. Completers could receive open-label glycopyrronium tosylate for up to an additional 44 weeks. Treatment-emergent adverse events and local skin reactions were assessed. Descriptive efficacy assessments were gravimetrically measured sweat production, Hyperhidrosis Disease Severity Scale responder rate (≥ 2 grade improvement), and Dermatology Life Quality Index/children's Dermatology Life Quality Index., Results: Of 651 patients completing the double-blind trials, 564 (86.6%) entered the open-label extension; 550 were analyzed. Most patients experiencing treatment-emergent adverse events had mild or moderate events (> 90%). Discontinuation because of treatment-emergent adverse events remained low and relatively stable, with a cumulative rate of 8.0% (44/550) over 44 weeks. Common treatment-emergent adverse events (> 5%) were dry mouth (16.9%), vision blurred (6.7%), application-site pain (6.4%), nasopharyngitis (5.8%), and mydriasis (5.3%). Most patients (67.5%) had no local skin reactions; those occurring were predominantly mild/moderate. Glycopyrronium tosylate efficacy was maintained throughout the trial; at week 44, the Hyperhidrosis Disease Severity Scale responder rate was 63.2%, and improvements from baseline (double blind) in sweat production were - 71.3% and 8.7 ± 6.2/6.2 ± 4.9 for Dermatology Life Quality Index/children's Dermatology Life Quality Index., Conclusions: Daily long-term application of glycopyrronium tosylate for up to 48 weeks (double blind plus open label) was generally well tolerated and efficacy was maintained. No new safety signals emerged., Trial Registry: Clinicaltrials.gov NCT02553798.

Background: Long-term use of inhaled corticosteroids (ICSs) has been associated with increased risk of bone and ocular comorbidities. We evaluated the effects of the triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, on bone mineral density (BMD) and ocular safety in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD)., Methods: In this extension study, a subset of patients from the 24-week, phase III, randomized, double-blind KRONOS study (NCT02497001) continued treatment (BGF MDI 320/18/9.6 μg, budesonide/formoterol fumarate [BFF] MDI 320/9.6 μg or glycopyrrolate/formoterol fumarate [GFF] MDI 18/9.6 μg, as a non-steroidal comparator) for an additional 28 weeks. Primary endpoints were percentage change from baseline in lumbar spine BMD and change from baseline in lens opacities classification system III posterior subcapsular cataract (P) score, both at Week 52. Adverse events were also assessed., Results: In total, 456 patients were included in the safety population (53.1% male, mean age 62.8 years). Changes from baseline in lumbar spine BMD (least squares mean [LSM] range - 0.12 to 0.38%) and P score (LSM range 0.02-0.15) were small for all treatments. Both BGF MDI and BFF MDI were non-inferior to GFF MDI using margins of -2% (BMD) and 0.5 units (P score). The incidence of treatment-emergent adverse events (TEAEs)  was generally similar among groups. Rates of confirmed pneumonia were low overall (2.4%) and highest in the GFF MDI group (3.4%), followed by BGF MDI (2.1%) and BFF MDI (1.1%). There were no cumulative adverse effects of treatment over time as the incidence and types of TEAEs, were generally similar in the first 24 weeks of the study and after Week 24., Conclusions: In patients with COPD, both ICS-containing therapies were non-inferior to GFF MDI for the primary BMD and ophthalmological endpoints. Changes from baseline in all three treatment groups over 52 weeks were small and not clinically meaningful. All treatments were well tolerated with no new or unexpected safety findings., Trial Registration: ClinicalTrials.gov NCT02536508. Registered 27 August 2015.

Background: Current pharmacological therapies for COPD improve quality of life and symptoms and reduce exacerbations. Given the progressive nature of COPD, it is arguably more important to understand whether the available therapies are able to delay clinical deterioration; the concept of "clinically important deterioration" (CID) has therefore been developed. We evaluated the efficacy of the single-inhaler triple combination beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G), using data from three large 1-year studies., Methods: The studies compared BDP/FF/G to BDP/FF (TRILOGY), tiotropium (TRINITY), and indacaterol/glycopyrronium (IND/GLY; TRIBUTE). All studies recruited patients with symptomatic COPD, FEV 1 <50%, and an exacerbation history. We measured the time to first CID and to sustained CID, an endpoint combining FEV 1 , St George's Respiratory Questionnaire (SGRQ), moderate-to-severe exacerbations, and death. The time to first CID was based on the first occurrence of any of the following: a decrease of ≥100 mL from baseline in FEV 1 , an increase of ≥4 units from baseline in SGRQ total score, the occurrence of a moderate/severe COPD exacerbation, or death. The time to sustained CID was defined as: a CID in FEV 1 and/or SGRQ total score maintained at all subsequent visits, an exacerbation, or death., Results: Extrafine BDP/FF/G significantly extended the time to first CID vs BDP/FF (HR 0.61, P <0.001), tiotropium (0.72, P <0.001), and IND/GLY (0.82, P <0.001), and significantly extended the time to sustained CID vs BDP/FF (HR 0.64, P <0.001) and tiotropium (0.80, P <0.001), with a numerical extension vs IND/GLY., Conclusion: In patients with symptomatic COPD, FEV 1 <50%, and an exacerbation history, extrafine BDP/FF/G delayed disease deterioration compared with BDP/FF, tiotropium, and IND/GLY., Trial Registration: The studies are registered in ClinicalTrials.gov: TRILOGY, NCT01917331; TRINITY, NCT01911364; TRIBUTE, NCT02579850., Competing Interests: Disclosure DS is supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC). DS received personal fees from Chiesi during the conduct of these studies. Outside the submitted work, DS reports grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Takeda, Teva, Theravance, and Verona, and personal fees from Genentech and Skyepharma. LMF reports grants, personal fees, and non-financial support from Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Takeda, AstraZeneca, Novartis, Menarini, Laboratori Guidotti, and Almirall; personal fees and non-financial support from Pearl Therapeutics, Mundipharma, and Boston Scientific; personal fees from Kyorin, Bayer, and Zambon; and grants from Pfizer, Dompè, Malesci, Alfasigma, and Vree Health Italia, all outside the submitted work. SV and SP are employed by Chiesi, the sponsor of the studies. AP reports grants, personal fees, non-financial support, and advisory board membership from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma, and TEVA; personal fees and non-financial support from Menarini, Novartis, and Zambon; and grants from Sanofi, all outside the submitted work. The authors report no other conflicts of interest in this work.

Purpose: Bronchodilator reversibility has been reported in patients with COPD, although correlations between reversibility and treatment response are unclear. The effect of reversibility on lung function, health status, and dyspnea was assessed in patients with moderate-to-severe COPD receiving glycopyrrolate (GLY) 15.6 µg twice daily vs placebo in the Glycopyrrolate Effect on syMptoms and lung function 1 and 2 (GEM1 and GEM2) replicate, 12-week, placebo-controlled studies., Patients and Methods: Reversibility was defined as a post-bronchodilator increase of ≥12% and ≥0.200 L in FEV 1 . FEV 1 area under the curve from 0 to 12 hours (AUC0-12 h), trough FEV 1 , St George's Respiratory Questionnaire (SGRQ) total score, COPD Assessment Test (CAT™) score, Transition Dyspnea Index (TDI) focal score, daily symptom scores, and rescue medication use were assessed by reversibility status. Incidences of adverse events and serious adverse events were also assessed., Results: Data from 846 patients enrolled in GEM1 and GEM2 with known reversibility status were pooled for post hoc analysis. GLY significantly improved FEV 1 AUC0-12 h, trough FEV 1 , SGRQ and CAT total scores, and rescue medication use compared with placebo in reversible and nonreversible patients. Significant improvements in TDI focal score and daily symptom scores with GLY over placebo were observed only among reversible patients. Improvements in FEV 1 AUC0-12 h (0.165 vs 0.078 L; P <0.001) and trough FEV 1 (0.173 vs 0.070 L; P <0.001) were clinically relevant (based on minimal clinically important differences) and significantly greater in reversible compared with nonreversible patients receiving GLY. The safety profile of GLY was not affected by reversibility status., Conclusion: In this post hoc analysis, GLY was associated with significant improvements in lung function and patient-reported outcomes compared with placebo, mostly independent of reversibility status. In patients receiving GLY, improvements in lung function were greater in reversible compared with nonreversible patients. Reversibility status did not meaningfully impact the safety profile of GLY., Competing Interests: Disclosure JAO has served on advisory boards for Sunovion Pharmaceuticals Inc., AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Mylan, and Theravance, and has provided expert witness testimony for Wallace & Graham; Levy Konigsberg; Goldenberg Heller & Antognoli; Simon Greenstone Panatier Bartlett; Williams Kherkher Hart; Gori Julian & Associates; Simmons Hanly Conroy; and Elrod Pope. AB, TG, BP, AO-G, SSh, and SSa are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work.

Background: Effective delivery of inhaled drugs in chronic obstructive pulmonary disease (COPD) depends on patients' ability to correctly use an inhalation device. Nebulized delivery may be appropriate for COPD patients who cannot coordinate breath with inhalation or generate adequate inhalational force. Until recently, long-acting muscarinic antagonists (LAMAs), used for maintenance treatment of COPD, were available for delivery only via handheld inhalers. Lonhala™ Magnair™ (glycopyrrolate inhalation solution) is a LAMA delivered via the eFlow ® closed-system (eFlow CS) vibrating membrane nebulizer. We assessed patient-reported ease of use and satisfaction with the eFlow CS nebulizer in the GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer)-5 study., Methods: GOLDEN-5, a phase 3, randomized, open-label trial, evaluated the safety and efficacy of glycopyrrolate/eFlow CS 50 μg twice daily versus tiotropium 18 μg once daily (administered via HandiHaler™) in patients with moderate-to-very severe COPD. Only patients in the glycopyrrolate/eFlow CS group completed a study-specific device use questionnaire, evaluating patients' perceptions about ease of use, confidence in drug delivery, and overall device satisfaction at week 48 or end of study. Responses were summarized by counts and percentages., Results: Of 620 patients who received glycopyrrolate/eFlow CS, 454 completed the questionnaire (mean age [standard deviation, SD] 63.3 [8.5] years; mean BMI [SD] 28.45 [6.208] kg/m 2 ). Based on patient-reported perceptions, most patients (83%) were "confident" to "very confident" that the drug was delivered into their lungs with the eFlow CS; >70% rated the eFlow CS as "easy" or "very easy" to assemble, operate, and clean. Most (75%) patients ranked themselves as being "satisfied" or "very satisfied" overall with the eFlow CS nebulizer., Conclusions: High levels of satisfaction, confidence, and ease of use were reported with the eFlow CS nebulizer in this study. These findings support the use of the eFlow CS for maintenance treatment of COPD with glycopyrrolate inhalation solution.

Background: GFF MDI is a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler formulated using co-suspension delivery technology. This open-label, single-arm multicenter study (NCT02268396) evaluated the accuracy, reliability, and functionality of the GFF MDI AeroCount ® dose indicator when used by patients with chronic obstructive pulmonary disease (COPD)., Patients and Methods: The study enrolled subjects (40-80 years of age) with an established clinical history (≥6 months) of COPD, who completed an electronic diary twice daily to record study-drug administration time, the number of actuations used, and pre- and post-dose dose indicator readings. The primary endpoint was the percentage of devices for which the number of subject-reported actuations was consistent (±20 actuations) with the dose indicator-based actuation count (equal to 130 minus the dose indicator reading) at the end of the treatment period (4 weeks). Safety was monitored throughout the study., Results: A total of 138 subjects with moderate-to-very severe COPD (50.7% male; mean [standard deviation (SD)] age 62.1 [8.3] years) were enrolled and treated. Subject-reported actuation count and dose indicator-based actuation counts were consistent for 96.4% (132/137) of devices at the end of the treatment period (4 weeks) in the intent-to-treat (ITT) population and for all devices in the per-protocol (PP) population. The mean (SD) dose indicator-based actuation and subject-reported actuation counts in the ITT population (n = 137) were 113.4 (18.9) and 117.0 (19.0), respectively, with a mean (SD) difference of 3.6 (7.9). The mean (SD) dose indicator-based actuation and subject-reported actuation counts in the PP population (n = 112) were 116.8 (8.7) and 119.7 (8.1), respectively. There were no unexpected safety findings., Conclusions: This study supported the accuracy, reliability, and utility of the dose indicator integrated into the GFF MDI device when used by patients with COPD.

Purpose: In contrast to randomized controlled trials (RCTs), changes in maintenance pharmacotherapy in clinical practice occur without a washout period. The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada (POWER) study evaluated the real-life effectiveness of indacaterol/glycopyrronium (IND/GLY) following a direct switch from a long-acting muscarinic antagonist (LAMA, tiotropium) or long-acting β 2 -agonist (LABA)/inhaled corticosteroid (ICS) maintenance treatment (salmeterol/fluticasone [SFC])., Methods: POWER was a single-cohort, prospective, multicenter, interventional study in which patients with moderate-to-severe COPD, who remained symptomatic on their current treatment of once-daily (od) tiotropium 18 µg or twice-daily (bid) SFC (any dose), were switched to treatment with open-label IND/GLY 110/50 µg od for 16 weeks. Effectiveness end points were change from baseline in trough FEV 1 , transition dyspnea index (TDI) total scores, and COPD assessment test (CAT) scores at 16 weeks., Results: Trough FEV 1 improved by 175 mL at Week 16 in patients who switched to IND/GLY. The change was 176 mL (95% CI: 135-217) when switched from tiotropium and 172 mL (95% CI: 85-258) when switched from SFC fixed-dose combination (FDC). At Week 16, significant improvements were observed in the mean TDI total scores (Δ=2.5) and CAT scores (Δ=-6.5) after the switch to IND/GLY treatment (both P <0.0001). Additionally, IND/GLY was well tolerated in patients with moderate-to-severe COPD, and no safety signal was observed., Conclusion: In clinical practice settings, a direct switch from previous treatment with either tiotropium or SFC to IND/GLY was safe and provided superior clinically significant improvements in lung function and patient-related outcomes in patients with moderate-to-severe COPD., Clinical Trial Registration: NCT02202616., Competing Interests: Disclosure AK reports nonfinancial support from Novartis, during the conduct of the study; personal fees from Novartis, Boehringer Ingelheim, AstraZeneca, Teva, Pfizer, Sanofi, Purdue, and Paladdin; and grants and personal fees from Benton Dickinson, outside the submitted work. KRC reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants from Baxter, grants and personal fees from CSL Behring, grants and personal fees from Grifols, grants from GlaxoSmithKline, grants and personal fees from Sanofi, grants and personal fees from Genentech, grants and personal fees from Kamada, grants from Amgen, grants and personal fees from Roche, grants and personal fees from Novartis, personal fees from Merck, and personal fees from CIHR-GSK Research Chair in Respiratory Health Care Deliveryat the University Health Network, during the conduct of the study. IM reports honoraria for continuing medical education related to COPD and asthma. DR is an employee of and reports personal fees from Novartis Pharmaceuticals Canada Inc. MD was a former employee of Novartis Pharmaceuticals Canada Inc. during this study. SMA reports clinical trial fees and speaking fees from Novartis. DP is an employee of and reports personal fees from Novartis Pharmaceuticals Canada Inc. DP also reports personal fees from Novartis Pharma AG, during the conduct of the study. AM reports honoraria for attending advisory boards and providing CME for AstraZeneca, Boehringer Ingelheim, Novartis, and Takeda. The authors report no other conflicts of interest in this work.

Background: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) often coexist. Moreover, elderly patients suffering from HF have a higher incidence of COPD, which further complicates their clinical condition. Indacaterol/glycopirronium has shown benefits in the treatment of COPD, with few cardiologic adverse effects. We evaluated the safety and efficacy of this therapy in patients with history of HF., Methods: We enrolled 56 patients with a history of HF (New York Heart Association [NYHA] classes II and III) and stable COPD. We evaluated blood samples, clinical assessment, echocardiograms and basal spirometry at baseline and after 6 months of therapy with indacaterol/glycopirronium. In addition, the number of re-hospitalizations during the treatment period was evaluated., Results: The treatment was well tolerated. Brain natriuretic peptide (BNP) levels were significantly reduced compared with baseline (p < 0.001) after 6 months of treatment, and a higher percentage of patients improved their clinical status compared with baseline (p < 0.001). Minor changes were noted in the hemodynamic and metabolic parameters. Significant improvements in the echocardiographic parameters were noted in HF with reduced ejection fraction (HFrEF) patients. All respiratory parameters (forced expiratory volume in 1 s [FEV1], FEV1/forced vital capacity [FVC] ratio and COPD Assessment Test [CAT] scores) improved significantly (p < 0.001). No hospitalizations owing to HF or COPD exacerbation occurred. One patient died of respiratory failure., Conclusion: Indacaterol/glycopirronium was well-tolerated and effective in the treatment of COPD in this cohort of patients with a history of HF. Further studies are needed to clarify whether this compound can have a direct role in improving overall cardiovascular function.

Purpose: This study investigated the effect of dual bronchodilation with the long-acting β-receptor agonist/long-acting muscarinic antagonist combination, indacaterol/glycopyrronium (IND/GLY), on nighttime oxygenation, lung function, sleep quality, and symptoms in patients with moderate-to-severe COPD., Patients and Methods: This was a 4-week, double-blind, multicenter, placebo-controlled, two-period crossover study. Patients were randomized in a 1:1 ratio to receive IND/GLY 110/50 µg once daily or matching placebo. The primary objective was to evaluate the effect of treatment with IND/GLY on mean nighttime oxygenation, compared with placebo. The secondary objective was to determine the time spent <90% in blood oxygen saturation (SpO 2 ) compared with placebo. Exploratory objectives were to assess the effect of IND/GLY, compared with placebo, on sleep quality measured by the Medical Outcomes Study (MOS) Sleep Scale and the COPD and Asthma Sleep Impact Scale (CASIS) questionnaires and on symptoms assessed by COPD Assessment Test (CAT) questionnaire., Results: In total, 38 patients were randomized (n=22, IND/GLY; n=16, placebo). The change in nighttime oxygenation (SpO 2 ) was similar, and there was a comparable difference in time spent <90% SpO 2 between IND/GLY and placebo. Increases from baseline for the difference between IND/GLY and placebo for trough FEV 1 , FVC, and inspiratory capacity ( P <0.05) were seen, with a corresponding reduction in residual volume and functional residual capacity ( P <0.05). IND/GLY treatment showed an improvement in scores for CAT ( P =0.0208), CASIS, and the MOS Sleep Scale measures, Sleep Problems Index I, Sleep Problems Index II ( P =0.0315), Sleep Adequacy, Sleep Disturbance Scale, Somnolence Scale, and Short of Breath Scale ( P =0.0031)., Conclusion: In this study, IND/GLY 110/50 µg once daily improved symptoms, sleep quality, and lung function, but showed no effect on nighttime oxygenation in patients with moderate-to-severe COPD., Competing Interests: Disclosure Dr Lehmann reports fees to employer and other support from Novartis, during the conduct of the study. Dr Løkke reports, other than from Novartis during the conduct of the study, personal fees and nonfinancial support from Astra-Zeneca; grants, personal fees, and nonfinancial support from Boehringer Ingelheim; personal fees and nonfinancial support from GlaxoSmithKline; personal fees and nonfinancial support from Novartis; personal fees and nonfinancial support from Chiesi; and grants, personal fees, and nonfinancial support from Pfizer, outside the submitted work. The institution of Dr Grote received payments under the clinical trial agreement with Novartis during the conduct of the study. Dr Hedner reports no financial conflict of interest; he has one patent related to pharmacological therapy in sleep apnea pending and one issued. The authors report no other conflicts of interest in this work.

Objectives: Hyperhidrosis in pediatric patients has been understudied. Post hoc analyses of two phase 3 randomized, vehicle-controlled, 4-week trials (ATMOS-1 [NCT02530281] and ATMOS-2 [NCT02530294]) were performed to assess efficacy and safety of topical anticholinergic glycopyrronium tosylate (GT) in pediatric patients., Methods: Patients had primary axillary hyperhidrosis ≥ 6 months, average Axillary Sweating Daily Diary (ASDD/ASDD-Children [ASDD-C]) Item 2 (sweating severity) score ≥ 4, sweat production ≥ 50 mg/5 min (each axilla), and Hyperhidrosis Disease Severity Scale (HDSS) ≥ 3. Coprimary end points were ≥ 4-point improvement on ASDD/ASDD-C Item 2 (a validated patient-reported outcome) and change in gravimetrically measured sweat production at Week 4. Efficacy and safety data are shown through Week 4 for the pediatric (≥ 9 to ≤ 16 years) vs older (> 16 years) subgroups., Results: Six hundred and ninety-seven patients were randomized in ATMOS-1/ATMOS-2 (GT, N = 463; vehicle, N = 234); 44 were ≥ 9 to ≤ 16 years (GT, n = 25; vehicle, n = 19). Baseline disease characteristics were generally similar across subgroups. GT-treated pediatric vs older patients had comparable improvements in ASDD/ASDD-C Item 2 (sweating severity) responder rate, HDSS responder rate (≥ 2-grade improvement]), sweat production, and quality of life (mean change from Baseline in Dermatology Life Quality Index [DLQI]/children's DLQI), with greater improvement vs vehicle. Treatment-emergent adverse events were similar between subgroups, and most were mild, transient, and infrequently led to discontinuation., Conclusions: Topical, once-daily GT improved disease severity (ASDD/ASDD-C, HDSS), sweat production, and quality of life (DLQI), with similar findings in children, adults, and the pooled population. GT was well tolerated, and treatment-emergent adverse events were qualitatively similar between subgroups and consistent with other anticholinergics., (© 2018 The Authors. Pediatric Dermatology Published by Wiley Periodicals, Inc.)

Background: Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting β 2 -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 1 ), 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 1 [trough, peak, and area under the curve (AUC) 0-4 ], SGRQ total score and TDI focal score at week 24, and annualized rate of moderate-to-severe exacerbations, were observed versus 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.

Background: The efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY), administered twice daily (BID) via the innovative eFlow ® Closed System nebulizer (PARI Pharma GmbH, Starnberg, Germany), were demonstrated in two replicate, placebo-controlled, 12-week Phase III studies (GOLDEN 3 and GOLDEN 4). This report evaluates the efficacy and safety of GLY by baseline disease severity and age in the pooled GOLDEN 3 and GOLDEN 4 patient population (N=1,294)., Methods: Patients were grouped by baseline predicted post-bronchodilator FEV 1 (<50%, ≥50%) and age (<65, ≥65, ≥75 years)., Results: GLY (25 and 50 μg BID) produced significant improvements in trough FEV 1 in FEV 1 % predicted <50% (0.070 L, 0.079 L) and ≥50% (0.112 L, 0.126 L) subgroups ( P <0.01 vs placebo), and in patients aged <65 (0.056 L, 0.086 L), ≥65 (0.140 L, 0.124 L), and ≥75 (0.144 L, 0.120 L) years ( P <0.05 vs placebo). St George's Respiratory Questionnaire (SGRQ) total score was significantly improved with GLY 25 and 50 μg BID ( P <0.05 vs placebo) in FEV 1 % predicted <50% (-3.237, -3.061) and ≥50% (-3.392, -2.322) and in <65 years (-3.447, -2.318) and ≥65 years (-3.053, -3.098) subgroups. In patients aged ≥75 years, GLY 25 μg reduced SGRQ total score by -6.278 units ( P <0.01 vs placebo). The incidence of treatment-emergent adverse events was similar between GLY and placebo across all subgroups, and the overall incidence of cardiovascular events was low., Conclusions: Nebulized GLY improved lung function and health status and was well tolerated over 12 weeks in patients with moderate-to-very-severe COPD, irrespective of baseline disease severity and age., Clinical Trial Registration: NCT02347761, NCT02347774., Competing Interests: Disclosure Jill Ohar has served on advisory boards for Sunovion Pharmaceuticals Inc., AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Mylan, and Theravance, and has provided expert witness testimony for: Wallace & Graham, Levy Konigsberg, Goldenberg Heller & Antognoli, Simon Greensone Panatier Bartlett, Williams Kherkher Hart, Gori Julian & Associates, Simmons Hanley Conroy, and Elrod Pope. Robert Tosiello, Thomas Goodin, and Shahin Sanjar are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work.

Background: Chronic obstructive pulmonary disease (COPD) causes significant mortality in Japan. GFF MDI is a long-acting muscarinic antagonist/long-acting β 2 -agonist fixed-dose combination of glycopyrronium (GP) and formoterol fumarate dihydrate (FF), delivered by a metered dose inhaler (MDI) using co-suspension delivery technology, for the long-term maintenance treatment of COPD., Methods: This randomized, Phase I, single-dose, four-treatment, four-period, crossover study (NCT02196714) examined the pharmacokinetic (PK) and safety profile of two doses of GFF MDI (28.8 μg/10 μg and 14.4 μg/10 μg) and two doses of GP MDI (28.8 μg and 14.4 μg), both formulated using co-suspension delivery technology, in healthy Japanese subjects (18-45 years of age). PK parameters included area under the curve (AUC) from 0 to 12 h (AUC 0-12 ), AUC from 0 to the time of the last measurable plasma concentration, maximum observed plasma concentration (C max ), and time to C max . Safety was monitored throughout the study., Results: Plasma GP profiles were comparable between GFF MDI and GP MDI formulations containing the same GP dose. Increases in GP AUC 0-12 and C max were generally dose proportional from 14.4 to 28.8 μg after administration of either formulation., Conclusions: The addition of FF 10 μg to GP MDI 28.8 μg or 14.4 μg in a fixed-dose combination did not appreciably alter the PK of GP, nor did an increase in GP dose from 14.4 μg to 28.8 μg in a fixed-dose combination with FF 10 μg appreciably alter the PK of formoterol. Both formulations of GFF MDI and GP MDI were well tolerated in healthy Japanese subjects. Data from this study support further evaluation of GFF MDI in Japanese patients with COPD., (Copyright © 2018 Pearl \\u0013 a member of the AstraZeneca group. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: Combination long-acting β 2 -agonist/long-acting muscarinic antagonist (LABA/LAMA) has demonstrated superior clinical outcomes over LABA/inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) patients; however, data from blinded randomized controlled trials on direct switching from LABA/ICS to LABA/LAMA are lacking. FLASH (Assessment of switching salmeterol/Fluticasone to indacateroL/glycopyrronium in A Symptomatic COPD patient coHort) investigated if direct switch, without a washout period, from salmeterol/fluticasone (SFC) to indacaterol/glycopyrronium (IND/GLY) in COPD patients improves lung function and is well tolerated., Methods: In this 12-week, multicentre, double-blind study, patients with moderate-to-severe COPD and up to one exacerbation in previous year, receiving SFC for ≥3 months, were randomized to continue SFC 50/500 μg twice daily (bd) or switch to IND/GLY 110/50 μg once daily (od). Primary endpoint was pre-dose trough forced expiratory volume in 1 s (FEV 1 ) at Week 12., Results: In total, 502 patients were randomized (1:1) to IND/GLY or SFC. Patients switched to IND/GLY demonstrated superior lung function (pre-dose trough FEV 1 ) versus SFC at Week 12 (treatment difference (Δ) = 45 mL; P = 0.028). IND/GLY provided significant improvements in pre-dose trough forced vital capacity (FVC; Δ = 102 mL; P = 0.002) and numerical improvements in transition dyspnoea index (TDI; Δ = 0.46; P = 0.063). Rescue medication use and COPD assessment test (CAT) scores were comparable between groups. Both treatments had similar safety profiles., Conclusion: FLASH demonstrated that a direct switch to IND/GLY from SFC improved pre-dose FEV 1 and FVC in COPD patients with up to one exacerbation in the previous year. No new safety signals were identified., (© 2018 Asian Pacific Society of Respirology.)

Background: Indacaterol 27.5 µg/glycopyrrolate 15.6 µg (IND/GLY 27.5/15.6 µg) inhalation powder, a twice-daily, fixed-dose combination of a long-acting beta2-agonist (LABA) and a long-acting antimuscarinic antagonist (LAMA), is indicated in the US for long-term maintenance treatment of airflow obstruction in patients with COPD. The safety and efficacy of IND/GLY 27.5/15.6 µg have been established, but cost-effectiveness is not yet known. This study compared the cost-effectiveness of IND/GLY 27.5/15.6 µg with other long-acting COPD maintenance therapies., Methods: A Markov model was constructed from the US payer perspective. Health states were defined as mild (post-bronchodilator FEV 1 ≥80% of predicted), moderate (50% ≤FEV 1 <80% of predicted), severe (30% ≤FEV 1 <50% of predicted), and very severe (FEV 1 <30% of predicted) COPD. Patients entering the model transitioned through health states based on placebo-adjusted change from baseline in trough FEV 1 for each comparator at week 12. Comparators included other US Food and Drug Administration-approved LABA/LAMA fixed-dose combinations as well as commonly prescribed LAMA and LABA/inhaled corticosteroid agents. One-way and probabilistic sensitivity analyses were conducted to test the model assumptions and the overall robustness of the results., Results: Using the model, IND/GLY 27.5/15.6 µg treatment for 12 weeks resulted in total costs of US $23,375 vs US $9,365 for placebo. Compared with placebo, IND/GLY 27.5/15.6 treatment resulted in the highest improvement in FEV 1 across all comparators and the lowest cost per decline in 100 mL FEV 1 . IND/GLY 27.5/15.6 µg was also among the most cost-effective treatment option as measured by St George's Respiratory Questionnaire response rate, at US $3,518 per additional responder at 12 weeks compared with placebo. In addition, IND/GLY 27.5/15.6 µg had the lowest cost per severe exacerbation avoided vs placebo across all comparators (US $87,686)., Conclusion: This model, developed from the US payer perspective with a 5-year time horizon, found IND/GLY 27.5/15.6 µg to be a cost-effective treatment option for patients with moderate to severe COPD., Competing Interests: Disclosure KR was an employee of Sunovion Pharmaceuticals Inc at the time the study was conducted. CD is an employee of Sunovion Pharmaceuticals Inc. JM and AK are employees of Novartis Pharmaceuticals Corporation. LB was an employee of Xcenda LLC when the study was conducted. The authors report no other conflicts of interest in this work.

Neostigmine is the anticholinesterase drug most commonly used to reverse blockade or speed up recovery from neuromuscular blockade from nondepolarizing neuromuscular blocking drugs. Because of its cardiac muscarinic effects, prior or simultaneous administration of glycopyrrolate or atropine is usually recommended. There have been a few case reports of bradycardia, atrio-ventricular (AV) block, and cardiac arrest following neostigmine/glycopyrrolate administration to reverse neuromuscular block affecting several patients. In this report, we describe a case of 21-year-old with a history of seizure disorder and developmental delay that presented for dental surgery under general anesthesia and developed type I AV block following the simultaneous administration of neostigmine and glycopyrrolate to reverse a nondepolarizing neuromuscular block with rocuronium at the end of his surgery. We suggest that the chronic use of antiepileptic drugs in this patient in combination with neostigmine and glycopyrrolate lead to AV block in this patient. We also review similar cases reported in the literature and suggest an explanation for this observed phenomenon.

Introduction: BGF MDI, a budesonide, glycopyrronium, and formoterol fumarate dihydrate triple fixed-dose combination metered dose inhaler formulated using co-suspension delivery technology, is currently in Phase III global development for chronic obstructive pulmonary disease., Methods: This was a Phase I, randomized, double-blind, placebo-controlled, ascending-dose, crossover study to assess the safety and pharmacokinetic profiles of two doses of BGF MDI in healthy adult subjects of Japanese descent (NCT02197975). Safety assessments included monitoring for adverse events (AEs). Pharmacokinetic parameters were assessed following a single dose and 7-days chronic dosing with BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg., Results: Twenty subjects were randomized and included in the safety and pharmacokinetic populations; mean age 29.7 years; 65% male; and mean body mass index of 21.9 kg/m 2 . The incidences of treatment-emergent AEs (TEAEs) were similar between treatments. All the TEAEs were mild to moderate in severity. Budesonide area under the plasma concentration-time curve from 0 to 12 h (AUC 0-12 ) and maximum observed plasma concentration (C max ) values were approximately double for the higher dose of BGF MDI compared with the lower dose on Day 1 and also following chronic dosing on Day 8. Glycopyrronium and formoterol AUC 0-12 and C max values on Day 8 were comparable between the two doses of BGF MDI., Discussion: Both doses of BGF MDI were well tolerated in healthy subjects of Japanese descent and the systemic exposure to budesonide was dose proportional for BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg. The safety and pharmacokinetics for BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg in Japanese subjects were comparable to data from previous studies in Western populations, which suggests that the safety and efficacy profile of BGF MDI should be similar in Western and Japanese subjects., (Copyright © 2018 Pearl \\u0013 a member of the AstraZeneca group. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 µg) using innovative co-suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 µg and formoterol fumarate (FF) MDI 9.6 µg, in patients with moderate-to-severe COPD., Methods: In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV 1 ) area under the curve from 0 to 12 hours (AUC 0-12 ) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV 1 through 2 hours; time to onset of action (≥10% improvement in mean FEV 1 ); proportion of patients achieving ≥12% improvement in FEV 1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV 1 ; peak change from baseline in FEV 1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV 1 on Day 7. Safety was assessed., Results: All 185 randomized patients received treatment. All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 µg (all P ≤0.0137). For peak change in FEV 1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 µg. No significant differences were observed between GFF MDI and FF MDI 9.6 µg for primary and secondary endpoints. The incidence of adverse events was similar between treatments., Conclusion: While all doses of GFF MDI were superior to GP MDI 36 µg for the primary end-point, in this study neither superiority of GFF MDI to FF MDI 9.6 µg nor a clear dose-response was observed. All treatments were well tolerated with no unexpected safety findings., Competing Interests: Disclosure CR is Chief Executive Officer of Pearl – a member of the AstraZeneca Group, and an employee of AstraZeneca. JP has received speaking fees from AstraZeneca, Genentech, Pfizer, and others, and has conducted trials on behalf of Boehringer Ingelheim, Forest, GlaxoSmithKline, Merck, Novartis, Sunovion, Teva, and others. EMK has served on advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca, Forest, Mylan, Novartis, Oriel, Pearl – a member of the AstraZeneca Group, Sunovion, Teva, and Theravance. He has conducted multicenter clinical trials for ~40 pharmaceutical companies. ESR and PD are employees of Pearl – a member of the AstraZeneca Group. The authors report no other conflicts of interest in this work.

Long-acting muscarinic antagonists (LAMAs), along with long-acting β 2 -agonists (LABAs), are the mainstay for treatment of patients with COPD. Glycopyrrolate, or glycopyrronium bromide, like other LAMAs, inhibits parasympathetic nerve impulses by selectively blocking the binding of acetylcholine to muscarinic receptors. Glycopyrrolate is unusual in that it preferentially binds to M 3 over M 2 muscarinic receptors, thereby specifically targeting the primary muscarinic receptor responsible for bronchoconstriction occurring in COPD. Inhaled glycopyrrolate is slowly absorbed from the lungs and rapidly eliminated from the bloodstream, most likely by renal excretion in its unmetabolized form, limiting the potential for systemic adverse events. Inhaled glycopyrrolate is a fast-acting, efficacious treatment option for patients with moderate-severe COPD. It improves lung function, reduces the risk of exacerbations, and alleviates the symptoms of breathlessness, which in turn may explain the improvement seen in patients' quality of life. Inhaled formulations containing glycopyrrolate are well tolerated, and despite being an anticholinergic, few cardiovascular-related events have been reported. Inhaled glycopyrrolate is thus of value as both monotherapy and in combination with other classes of medication for maintenance treatment of COPD. This review covers the mechanism of action of inhaled glycopyrrolate, including its pharmacokinetic, pharmacodynamic, and safety profiles, and effects on mucus secretion. It also discusses the use of inhaled glycopyrrolate in the treatment of COPD, as monotherapy and in fixed-dose combinations with LABAs and inhaled corticosteroid-LABAs, including a triple therapy recently approved in Europe., Competing Interests: Disclosure DPT serves on advisory boards for AstraZeneca, Sunovion, Mylan, and Theravance/Innoviva, and as a speaker for AstraZeneca, Boehringer-Ingelheim, and Sunovion. NJG has no conflicts of interest.

Objectives: This randomized, double-blind, placebo-controlled, cross-over, Phase II dose-ranging study investigated the efficacy and safety of GP MDI (glycopyrronium administered by metered dose inhaler formulated using co-suspension delivery technology) compared with an open-label active comparator, salmeterol dry powder inhaler (SAL DPI), in subjects with intermittent or mild-to-moderate persistent asthma., Methods: Subjects were randomized to receive five of seven treatments (GP MDI 28.8, 14.4, 7.2, 3.6, and 1.9 μg, placebo MDI, and SAL DPI 50 μg), each for a 14-day period. The primary endpoint was peak change from baseline in forced expiratory volume in 1 s (FEV 1 ) on Day 15. Secondary endpoints included additional lung function parameters and symptoms (Asthma Control Questionnaire-5). Safety was monitored throughout., Results: Of 248 subjects randomized, 211 completed the study. All doses of GP MDI resulted in significant improvements in the primary endpoint compared with placebo MDI in a dose-ordered fashion (range 85-155 mL, p < .0001), without appreciable differences between the two highest doses of GP MDI (28.8 and 14.4 μg) and SAL DPI 50 μg. Improvements in secondary lung function endpoints and symptoms were generally dose-ordered, with GP MDI 28.8 μg showing the greatest improvements. Similar results were observed when endpoints were analyzed based on subjects' background use of inhaled corticosteroids (yes/no). All GP MDI doses were well tolerated with no evidence of a dose-related effect on adverse events., Conclusions: The results of this study suggest that GP MDI could offer an important treatment option for maintenance therapy of asthma, and warrants further investigation in Phase III clinical trials., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study compared the efficacy, pharmacokinetics (PK), and safety of GFF MDI (Bevespi Aerosphere ® ), a fixed-dose combination of glycopyrronium and formoterol fumarate dihydrate (14.4/10 μg) delivered by a metered dose inhaler (MDI) formulated using innovative co-suspension delivery technology, in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) with and without the Aerochamber Plus ® Flow-Vu ® valved holding chamber (VHC)., Methods: In this multicenter, open-label, crossover, Phase III study (NCT02454959), patients were randomized to receive GFF MDI 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) twice daily for 7 days with and without the VHC. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV 1 AUC 0-12 ) on Day 8. Steady state PK parameters for glycopyrronium and formoterol (AUC 0-12 , peak concentration [C max ] and time to peak concentration [t max ]) were estimated from 12-h plasma concentration time data on Day 8. Safety and tolerability were also assessed throughout., Results: Eighty patients were randomized. On Day 8, the ratio (90% confidence interval [CI]) of least squares mean (LSM) FEV 1 AUC 0-12 for GFF MDI with VHC (LSM = 1538 mL; n = 67) versus without VHC (LSM = 1516 mL; n = 68) was 101.4% (100.1, 102.7). PK parameters were comparable overall with a slightly higher exposure to glycopyrronium with the VHC. The AUC 0-12 geometric LSM ratio (90% CI) for GFF MDI with versus without VHC was 115.99% (99.74, 134.89) for glycopyrronium and 96.66% (86.69, 107.78) for formoterol. GFF MDI with and without VHC were well tolerated with a similar adverse event profile., Conclusions: The magnitude of bronchodilatory effect was similar with and without a VHC following GFF MDI treatment. This, together with the PK and safety profiles, supports the use of the VHC with GFF MDI for the maintenance treatment of COPD, which could be particularly useful for patients who have difficulty with the coordination of an MDI., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function. Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy. This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting β 2 -agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID., Methods: CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings. Three definitions of CID (D1-D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV 1 ), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD). In D1 and D2, either TDI or CCQ was evaluated along with FEV 1 and AECOPD, whereas in D3, all 4 parameters were included. ClinicalTrials.gov number: NCT01985334., Results: Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments. The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]). Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89])., Conclusion: In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice., Competing Interests: Disclosure TG has received compensation from Novartis during the conduct of the study. He has also received lecture fees from AstraZeneca, Chiesi, CSL-Behring, GlaxoSmithKline, Grifols, Mundipharma, and Novartis, and received compensation for organizing or participating in advisory boards from AstraZeneca, CSL-Behring, Novartis, Boehringer Ingelheim and Grifols, and received a grant to support an AATD-Lab from Grifols. KK has previously received honoraria for speeches and consulting services from AstraZeneca, Chiesi, ELPEN, and Takeda, and received honoraria for speeches from Boehringer Ingelheim outside the submitted work. MG has received a grant and personal fees from Novartis, Pharmaten and Menarini, outside the sub mitted work. She has also received personal fees from Chiesi, Boehringer Ingelheim and Teva, and received compensation for organizing or participating in advisory boards from GlaxoSmithKline, and received a grant from AstraZeneca. XN and VAP were statisticians for this subgroup analysis of the CRYSTAL study and work at a Novartis contracted CRO. CFV has received personal fees from Novartis during the conduct of the study. Outside the submitted work, he has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Menarini, Mundipharma and Teva, and grants from GlaxoSmithKline and Grifols. KK is an employee and shareholder of Novartis Pharma AG. MA-M and NL are employees of Novartis Pharma AG. AC and FP are employees and shareholders of Novartis Pharma AG. RF is an employee and shareholder of Novartis Pharmaceutical Corporation. The authors report no other conflicts of interest in this work.

Purpose: Due to the burden of COPD in Japan, new pharmacologic treatments are needed to meet patient requirements. This study assessed the efficacy and safety of glycopyrronium (GP) delivered via metered dose inhaler (MDI) in Japanese patients with moderate-to-severe COPD., Methods: This Phase IIb, multicenter, randomized, double-blind, 7-day, crossover study compared GP MDI 28.8, 14.4, and 7.2 μg with placebo MDI (all administered as two inhalations, twice daily). The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV 1 ) on Day 8. Secondary endpoints included FEV 1 area under the curve from 0 to 2 hours (AUC 0-2 ) and peak change from baseline in FEV 1 on Days 1 and 8 and forced vital capacity AUC 0-2 on Day 8. Safety was also assessed. ClinicalTrials.gov Identifier: NCT03256552; http://www.ClinicalTrials.gov., Results: Sixty-six patients were randomized and 62 were included in the modified intent-to-treat population (mean age 67.5 years). All three GP MDI doses significantly improved change from baseline in morning pre-dose trough FEV 1 on Day 8 compared with placebo MDI (least squares mean differences 108-131 mL; all p <0.0001). Significant improvements in secondary efficacy endpoints were also observed for all three GP MDI doses compared with placebo MDI (all p <0.0001). Dose-response plateaued at GP MDI 14.4 μg. No significant safety findings were observed with any GP MDI dose or placebo MDI., Conclusions: The results of this study suggest that GP MDI 14.4 μg (7.2 μg per inhalation) is the most appropriate dose for use in Phase III studies in Japanese patients with moderate-to-severe COPD., Competing Interests: Disclosure ESR and AM are employees of Pearl – a member of the AstraZeneca Group. SS is an employee of AstraZeneca. CR is an employee of Pearl – a member of the AstraZeneca Group and an employee of AstraZeneca. The other authors report no conflicts of interest in this work.

Background: The FLAME study compared once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 μg with twice-daily salmeterol/fluticasone (SFC) 50/500 μg in symptomatic patients with moderate to very severe COPD and a history of exacerbations in the previous year., Methods: This prespecified and post hoc subgroup analysis evaluated treatment efficacy on 1) moderate/severe exacerbations according to prior exacerbation history and treatment, and 2) types of exacerbations according to health care resource utilization (HCRU) during 1-year follow-up., Results: IND/GLY reduced the rate of moderate/severe exacerbations versus SFC in patients with a history of 1 exacerbation (rate ratio [RR]: 0.83, 95% CI: 0.75-0.93), ≥2 exacerbations (RR: 0.85, 95% CI: 0.70-1.03) and ≥2 exacerbations or ≥1 hospitalization in the previous year (RR: 0.86, 95% CI: 0.74-1.00). Prolonged time-to-first exacerbation was observed in all the groups according to exacerbation history. Moderate/severe exacerbations decreased with IND/GLY versus SFC, independent of previous treatment. IND/GLY significantly reduced rates of moderate/severe exacerbations treated with antibiotics (RR: 0.79, 95% CI: 0.67-0.93) and systemic corticosteroids and antibiotics (RR: 0.80, 95% CI: 0.70-0.91); rates of exacerbations treated with systemic corticosteroids alone were comparable (RR: 0.99, 95% CI: 0.80-1.22)., Conclusion: Overall, IND/GLY demonstrated consistent beneficial effects versus SFC on moderate/severe exacerbations, independent of prior exacerbation history or treatment. The efficacy of IND/GLY on exacerbation prevention was superior to SFC for exacerbations treated with antibiotics with/without systemic corticosteroids and was similar for exacerbations treated with systemic corticosteroids alone., Competing Interests: Disclosure CFV has received grant funding, honoraria for lectures and/or participation in advisory boards from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Grifols, Menarini, Mundipharma, Novartis, Teva, and Cipla. KRC reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants from Baxter, grants and personal fees from CSL Behring, grants and personal fees from Grifols, grants from GlaxoSmithKline, grants and personal fees from Sanofi, grants and personal fees from Genentech, grants and personal fees from Kamada, grants from Amgen, grants and personal fees from Roche, grants and personal fees from Novartis, personal fees from Merck, personal fees from CIHR-GSK Research Chair in Respiratory Health Care Delivery, UHN, during the conduct of the study. NR has received grants and personal fees from Boehringer Ingelheim, Novartis, Pfizer; personal fees from Teva, GSK, AstraZeneca, Chiesi, Mundipharma, Cipla, Sanofi, Sandoz, 3M, and Zambon, outside the submitted work. JV reports personal fees from GlaxoSmithKline, Chiesi pharmaceuticals, Boehringer-Ingelheim, Novartis, Almirall, AstraZeneca, Bioxydyn, Ferring, outside the submitted work. MM has received speaker fees from Boehringer Ingelheim, Chiesi, Cipla, Menarini, Grifols and Novartis, and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Gebro Pharma, CLS Behring, Novartis and Grifols. JAW reports grants from GSK, grants from Johnson and Johnson, other from Novartis, other from Boehringer Ingelheim, other from Astra Zeneca, other from GSK, grants from GSK, grants from Astra Zeneca, grants from Boehringer Ingelheim, grants from Novartis, outside the submitted work. CT, DB, RF, FP and KK are employees and shareholders of Novartis Pharma AG. PO is an employee of Novartis AB and a Novartis shareholder. The authors report no other conflicts of interest in this work.

Objective: The aim of this study was to evaluate the cost-effectiveness of the long-acting beta-2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator indacaterol/glycopyrronium (IND/GLY) as a maintenance treatment for COPD patients from the perspective of health care payer in Taiwan., Patients and Methods: We adopted a patient-level simulation model, which included a cohort of COPD patients aged ≥40 years. The intervention used in the study was the treatment using IND/GLY, and comparators were tiotropium or salmeterol/fluticasone combination (SFC). Data related to the efficacy of drugs, incidence of exacerbation, and utility were obtained from clinical studies. Direct costs were estimated from claims data based on the severity of COPD. The cycle length was 6 months (to match forced expiratory volume in 1 second [FEV 1 ] data), and the time horizons included 1, 3, 5, 10 years, and lifetime. Deterministic and probabilistic sensitivity analyses were conducted to test the robustness of the model results. Costs were expressed in US dollars with a discount rate of 3.0%., Results: Compared to tiotropium and SFC, the incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year (QALY) gained of patients treated with IND/GLY were US$5,987 and US$14,990, respectively. One-way sensitivity analysis revealed that the improvement in FEV 1 provided by IND/GLY, the distribution of patients with regard to the severity of COPD, and acute exacerbation rate ratio were the key drivers behind cost-effectiveness. Adopting a willingness to pay of US$60,000 per QALY gained as the threshold, there was a 98.7% probability that IND/GLY was cost-effective compared to tiotropium. Similarly, there was a 99.9% probability that IND/GLY was cost-effective compared to SFC., Conclusion: As a maintenance treatment for COPD, we consider the dual bronchodilator IND/GLY as a cost-effective strategy when compared to either tiotropium or SFC., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GP), and the long-acting β 2 -agonist (LABA), formoterol fumarate (FF), delivered via metered dose inhaler using innovative co-suspension delivery technology. Here we report the results of two studies that examined the cardiovascular safety of GFF MDI., Methods: The thorough QT (TQT) study was a Phase I, randomized, double-blind, single-dose, crossover study to assess GFF MDI 18/9.6 (Bevespi Aerosphere ® ), GFF MDI 144/38.4 and GP MDI 144 μg, compared with placebo MDI and open-label moxifloxacin 400 mg (active control) in healthy volunteers (PT003009). The cardiovascular safety study in patients with chronic obstructive pulmonary disease (COPD) was a Phase IIb, randomized, multicenter, double-blind, 14-day dosing, parallel-group study to evaluate GFF MDI 36/9.6, GP MDI 36 and FF MDI 9.6 μg compared with open-label FF dry powder inhaler (DPI; Foradil ® Aerolizer ® ) 12 μg, in patients with moderate-to-severe COPD (PT003003 [NCT01349803])., Results: Seventy healthy volunteers were randomized in the TQT study. GFF MDI 144/38.4, GFF MDI 18/9.6 and GP MDI 144 μg all met the confidence interval-based criteria for negative QT prolongation potential. In the study in patients with COPD, 237 subjects were randomized and treated. GFF MDI 36/9.6, GP MDI 36, and FF MDI 9.6 μg did not result in clinically meaningful changes from baseline in 24-h mean heart rate at Day 14 (primary endpoint) or in any of the other Holter monitoring endpoints at Day 14, compared with FF DPI 12 μg., Conclusions: No clinically significant effects on cardiovascular safety occurred at therapeutic or supratherapeutic doses of GFF MDI, apart from a small and transient increase in heart rate following supratherapeutic dose of GFF MDI 144/38.4 μg. Furthermore, there were no unexpected safety findings reported in either healthy volunteers or patients with COPD., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The efficacy and tolerability of GFF MDI (Bevespi Aerosphere ® ), a fixed-dose combination of glycopyrronium (GP)/formoterol fumarate dihydrate (FF) 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) delivered by metered dose inhaler (MDI) using innovative co-suspension delivery technology, has been investigated in a Phase III clinical trial program (NCT01854645, NCT01854658, NCT01970878) in patients with COPD. Here, we present findings from a pharmacokinetic (PK) sub-study of NCT01854645 (PINNACLE-1)., Methods: PINNACLE-1 was a multicenter, randomized, double-blind, parallel-group, 24 wk chronic-dosing, placebo- and active-controlled study. The PK sub-study assessed the systemic accumulation of glycopyrronium and formoterol following administration of GFF MDI 14.4/10 μg, GP MDI 14.4 μg, or FF MDI 10 μg (all BID) for 12 wks. Plasma for PK analysis was collected for up to 12 h after dosing, on Day 1 and Week 12., Results: Of 2,103 patients randomized in PINNACLE-1, 292 participated in the PK sub-study. The plasma concentration-time profiles of glycopyrronium were similar following treatment with GFF MDI or GP MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 2.30-fold for glycopyrronium. The plasma concentration-time profiles of formoterol were similar following treatment with GFF MDI or FF MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 1.62-fold for formoterol., Conclusion: Overall, the results have characterized the accumulation of glycopyrronium and formoterol associated with GFF MDI, GP MDI, and FF MDI, and indicated that there were no meaningful PK interactions, whether drug-drug or due to formulation, between glycopyrronium and formoterol following treatment with GFF MDI formulated using co-suspension delivery technology., Competing Interests: Disclosure GTF reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Pearl – A member of the AstraZeneca Group, Sunovion, and Theravance. He has also received grants from Forest and personal fees from GlaxoSmithKline, Meda, Mylan, and Verona. RRR has received personal fees from AstraZeneca, Boehringer Ingelheim, Pearl – A member of the AstraZeneca Group, TEVA, Menarini, and Novartis; and grants/research support from Menarini. CR is an employee of AstraZeneca and Chief Executive Officer of Pearl – A member of the AstraZeneca Group. AM is an employee of Pearl – A member of the AstraZeneca Group. SS and UJM are employees of Astra-Zeneca. The authors report no other conflicts of interest in this work.

Indacaterol/glycopyrronium (IND/GLY) 110/50mcg was the first once-daily, long-acting β 2 -agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) approved in Europe for the treatment of chronic obstructive pulmonary disease (COPD). Development of IND/GLY was driven by the need to improve the standard of care for patients with this disease, in terms of symptom control and exacerbation frequency. IGNITE, an adaptive, comprehensive, and innovative Phase 3 development program, demonstrated the efficacy of IND/GLY in optimising bronchodilation, reducing symptoms, and reducing exacerbations in patients with COPD. IGNITE challenged contemporary thinking about the pharmacological treatment and management of patients with this disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cardiovascular (CV) comorbidities in patients with chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality, especially in old and very old subjects. The question if long-acting beta-agonist and long-acting muscarinic antagonist could be associated with the increased prevalence of CV-related adverse effects has puzzled, particularly in the past, specialists involved in the management of respiratory diseases. The safety of these compounds has scarcely been tested in patients aged ≥ 65 years with CV comorbidities, since randomized controlled trials rarely include this subpopulation. However, the fixed combination indacaterol/glycopyrronium has shown a favorable CV safety profile in both healthy volunteers and COPD patients. Thus, we aimed to assess the CV safety pro-- file of the fixed combination indacaterol/glycopyrronium 110/50 μg in a series of COPD patients aged ≥ 80 years with several comorbidities. Our results indicate that this combination is safe in the comorbid elderly, since no significant electrocardiographic abnormalities were recorded after the administration of the inhaled therapy. Only rare and nonclinically significant changes in heart rate and corrected QT interval duration were evident, mainly in females and in patients with concomitant impaired kidney function., (© 2018 S. Karger AG, Basel.)

Background: The objective of the FAVOR study was to evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus tiotropium on peak forced expiratory volume in 1 s (FEV 1 ) and also to investigate patient satisfaction and treatment preference., Methods: Patients with moderate-to-severe airflow limitation (FEV 1 /forced vital capacity ratio of <0.70), those with a COPD assessment test score of ≥10, and those who were maintained on tiotropium HandiHaler ® therapy prior to enrollment were recruited for the study, and randomized (1:1) to receive either 4 weeks open-label IND/GLY (110/50 μg) once daily followed by 4 weeks of tiotropium (18 μg) once daily or vice versa. The primary endpoint was FEV 1 1 h post-inhalation after 4 weeks of treatment. Other endpoints included patient's and physician's preference for treatment, patient's satisfaction evaluated using a study-specific questionnaire and the abbreviated Treatment Satisfaction Questionnaire for Medication, and safety and tolerability., Results: Eighty-seven out of 88 randomized patients completed the study and showed significantly higher FEV 1 1 h post-inhalation after 4 weeks of treatment with IND/GLY versus tiotropium (treatment difference =0.081 L; p =0.0017). IND/GLY was preferred over tiotropium among the patients (69.4% versus 30.6%, p =0.0004) and the physicians (81.6% versus 18.4%, p <0.0001). A higher proportion of the patients stated they were very satisfied or satisfied with IND/GLY versus tiotropium with regard to dyspnea reduction (79.3% versus 58.0%, respectively) and reduction of dyspnea on exertion (72.4% versus 43.2%, respectively). Patients treated with IND/GLY showed significant improvement in Treatment Satisfaction Questionnaire for Medication domain scores versus tiotropium. IND/GLY demonstrated a good safety and tolerability profile., Conclusion: This study indicated that, beyond FEV 1 , important patient-reported outcomes improved with the open-label dual bronchodilator IND/GLY when compared with tiotropium. This study suggests that individual patients felt the lung function benefits with IND/GLY compared with tiotropium, which, in turn, may also have contributed to the preference for IND/GLY., Competing Interests: Disclosure Dr Peter Kardos reports personal fees and study honoraria for his practice from Novartis during the conduct of the study; personal fees and other from AstraZeneca and Boehringer Ingelheim; and personal fees from Chiesi, GSK, Menarini, and Teva, outside the submitted work. Dr Ina Hagedorn-Peinz is an employee of Novartis Pharma GmbH and was in a medical role during the study conduct and in a commercial role during the manuscript development. The authors report no other conflicts of interest in this work.

Purpose: To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI)., Methods: Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 μg and once-daily UMEC/VI 62.5/25 μg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV 1 AUC 0-24 ). Rescue medication use, symptom control, and safety were assessed throughout., Results: Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV 1 AUC 0-24h at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of -20 mL in both studies: -26.9 and -34.2 mL, respectively (LS mean between-treatment differences: -11.5 and -18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information., Conclusions: IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).

The European Medicines Agency (EMA) has granted marketing authorisation for a pressurised metered dose inhaler (pMDI) containing beclometasone dipropionate, formoterol fumarate dihydrate and glycopyrronium bromide (Trimbow - Chiesi Pharmaceuticals) for the treatment of chronic obstructive pulmonary disease (COPD) in patients not adequately treated with a combination of an inhaled corticosteroid (ICS) and a long-acting beta 2 agonist (LABA). 1-3 The manufacturer claims that this is a significant treatment advance for COPD patients, and that the use of one inhaler should simplify therapy and, therefore, may improve adherence. 1 Here, we consider the evidence for this product for the management of patients with moderate to severe COPD, and how it fits with current management strategies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta 2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a "step-up" therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients., Competing Interests: Disclosure DS reports grants and personal fees from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Takeda, Teva, Theravance, and Verona and personal fees from Genentech and Skyepharma. OSU has received industry-academic funding from Boehringer Ingelheim, Chiesi, Edmond Pharma, GlaxoSmithKline, Mundipharma International and has received consultancy or speaker fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, Cipla, Edmond Pharma, GlaxoSmithKline, Napp, Novartis, Mundipharma International, Pearl Therapeutics, Roche, Sandoz, Takeda, UCB, Vectura and Zentiva. JV has received honoraria for consulting and presenting from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. AP reports grants, personal fees, non-financial support, and others from Chiesi, AstraZeneca, GlaxoSmith-Kline, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Takeda, Mundipharma and TEVA, personal fees and non-financial support from Menarini, Novartis and Zambon, and grants from Sanofi. MC received honoraria for consultancy from Chiesi Farmaceutici SpA. MSp, SP, and MSc are full-time employees of Chiesi Farmaceutici SpA. The authors report no other conflicts of interest in this work.