Benefits of budesonide/glycopyrronium/formoterol fumarate dihydrate on lung function and exacerbations of COPD: a post-hoc analysis of the KRONOS study by blood eosinophil level and exacerbation history.

BACKGROUND: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity. METHODS: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. RESULTS: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. CONCLUSIONS: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant.

INTRODUCTION: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. METHODS: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 µg [medium-strength BDP]; Study 2: 200/6/12.5 µg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC0-t) for the analytes were between 80 and 125 %. RESULTS: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0-t). In Study 1, GB AUC0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0-t, although not for Cmax. Both formulations were similarly well tolerated in all three studies. CONCLUSIONS: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.

Digitally monitored inhaled therapy: a 'smart' way to manage severe asthma?

INTRODUCTION: One of the fundamental challenges of managing patients with severe asthma is treatment adherence, particularly with inhaled corticosteroids. Adherence is difficult to measure objectively and poor adherence is associated with worse outcomes. In this study, assess the ability of a 'smart' inhaler to record adherence in severe asthma patients and measure the impact of this on asthma control. METHODS: Consecutive consenting patients meeting criteria for biologics had their existing high-dose ICS/LABA//LAMA combination inhaler/s switched to mometasone/indacaterol/glycopyrronium (114/46/136). Routine clinical data, including blood eosinophils, FeNO, and ACQ-6 scores were collected at baseline and at 4 wk. Adherence was then checked on the Propeller Health app, and good adherence was defined as >80% of prescribed usage. Participants were then followed-up at 12 months to record the proportion of patients who were initiated on biologics. RESULTS: 77 patients (mean [SD] age = 50.4 [15.7] years, 67.5% female [n = 52]) participated. 71 participants were able to use the device and 65% (n = 46) of these attained good asthma control and were not initiated on biologics at 12-month follow-up. Both groups demonstrated a significant reduction in ACQ6 score at follow-up (2.81 vs. 1.92, p < 0.001 and 3.05 vs. 2.60, p < 0.001, respectively), but there was no statistically significant difference in improvement between groups. Patients with optimal adherence also demonstrated a significant reduction in median FeNO at follow-up (47 ppb vs. 40 ppb, p = 0.003). CONCLUSIONS: In severe asthma patients, 'smart' inhalers may represent an effective management tool to improve adherence and asthma control, therefore avoiding the need for patients to commence biological therapies.

Glycopyrronium 320 µg/mL in children and adolescents with severe sialorrhoea and neurodisabilities: A randomized, double-blind, placebo-controlled trial.

AIM: To investigate the efficacy, safety, and impact on quality of life (QoL) of an oral formulation of 320 µg/mL glycopyrronium designed for children. METHOD: A double-blind, placebo-controlled SALIVA (Sialanar plus orAl rehabiLitation against placebo plus oral rehabilitation for chIldren and adolescents with seVere sialorrhoeA and neurodisabilities) trial was conducted. Children (3-17 years) with neurodisabilities and severe sialorrhoea (modified Teachers Drooling Scale ≥6) were randomized to 320 µg/mL glycopyrronium or placebo, in addition to non-pharmacological standard care. RESULTS: Of 87 participants, 44 were aged 10 years or under and 43 had cerebral palsy. The primary endpoint, change in total Drooling Impact Scale (DIS) score from baseline to day 84, was significantly greater (improved) with 320 µg/mL glycopyrronium versus placebo (median [quartile 1, quartile 3] -29.5 [-44.5, 0] vs -1 [-16, 5]; p < 0.001), an effect also observed at day 28 (median - 25 vs -2; p < 0.01). Significant reduction in bibs/clothes used per day was seen with glycopyrronium versus placebo at day 84 (median - 2 vs 0; p < 0.01). Glycopyrronium significantly improved DIS items 9 and 10 related to the extent that drooling affects the child's and family's life (p ≤ 0.03). Adverse events were reported by 77.3% and 69.8% of children with glycopyrronium and placebo respectively; the most common treatment-related adverse event was constipation (20.5% and 16.3%). INTERPRETATION: The formulation of 320 µg/mL glycopyrronium significantly improved drooling and reduced its impact on QoL, with good tolerability in children with neurodisabilities. WHAT THIS PAPER ADDS: The formulation of 320 µg/mL glycopyrronium significantly improved Drooling Impact Scale score versus placebo at day 84. The formulation reduced the impact of drooling on the child's and family's quality of life. There were no safety or tolerability concerns with this specific formulation.

[The effect of glycopyrrolate on intestinal spasm and hemodynamics in painless colonoscopy].

Objective: To investigate the effects of glycopyrrolate on intestinal spasm and hemodynamics in painless colonoscopy. Methods: A total of 100 patients who were scheduled to undergo painless colonoscopy were selected as the study subjects and randomly divided into two groups by a computerized number method. Ten patients in both groups dropped out because of disruption of the study protocol, and 45 patients from each group were included in the final analysis. Before anesthesia induction, patients in group glycopyrrolate (group G) were injected with 0.2 mg glycopyrrolate, while those in congtrol group (group C) were injected with an equal amount of saline. The heart rate, systolic blood pressure, and diastolic blood pressure were recorded at T0 (baseline period), T1 (after anesthesia induction), T2 (colonoscopy over sigmoid colon), T3 (colonoscopy over the liver region), T4 (after the end of examination), and T5 (at the awakening phase), and the degree of intestinal spasm was assessed intraoperatively using the Likert's four-point scale. The numerical rating scale (NRS) was used to assess preoperative and postoperative pain. The incidence of adverse events was recorded. Results: The general data at baseline were not statistically different between the two groups (P>0.05). During the procedure, patients in group G had lower intraoperative intestinal spasm scores than those in group C (P=0.028). Intraoperative hypotension and bradycardia occurrence were lower in group G than in group C (P<0.05), and intraoperative norepinephrine use was also lower than in the group C (P=0.034). Postoperative visual analog scale pain scores were lower in group G (P=0.047), but patients who used glycopyrrolate had a higher proportion of dry mouth (P=0.035). Conclusion: During painless colonoscopy, preoperative administration of glycopyrrolate significantly improved intraoperative hemodynamic fluctuations, reduced the incidence of hypotension and bradycardia, and relieved postoperative pain. However, glycopyrrolate use resulted in the risk of dry mouth.

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD.

BACKGROUND: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-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.).

Effect of indacaterol/glycopyrronium on ventilation and perfusion in COPD: a randomized trial.

RATIONALE: The long-acting ß2-agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY. OBJECTIVES: The primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured. METHODS: This double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days. MEASUREMENTS AND MAIN RESULTS: Of 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DLCO) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV1) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial. CONCLUSIONS: IND/GLY improved lung ventilation assessed by 3He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02634983).

Extrafine triple therapy and asthma exacerbation seasonality: TRIMARAN and TRIGGER post hoc analyses.

BACKGROUND: Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine formulations of the inhaled corticosteroid (ICS) beclomethasone dipropionate (BDP), long-acting ß2-agonist formoterol fumarate (FF), and long-acting muscarinic antagonist glycopyrronium (G) is in development for asthma. OBJECTIVE: We sought to evaluate whether calendar season impacted the relative effect of BDP/FF/G versus BDP/FF on moderate and severe asthma exacerbations. METHODS: TRIMARAN and TRIGGER were double-blind 52-week studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma (Asthma Control Questionnaire-7 score ≥1.5), prebronchodilator FEV1 less than 80% predicted, history of 1 or more asthma exacerbation, who had been receiving ICS/long-acting ß2-agonist for at least 4 weeks before entry. Moderate and severe asthma exacerbations were captured throughout each study. In these post hoc analyses, the annual moderate and severe exacerbation rate was calculated for each month, with rate ratios determined from events grouped by season. RESULTS: In patients who received BDP/FF alone, there was a marked seasonal effect on the occurrence of asthma exacerbations, with the rate highest in the winter months. However, the addition of the long-acting muscarinic antagonist component to BDP/FF reduced this seasonal variation, especially during the winter, such that the relative effect of BDP/FF/G versus BDP/FF was greatest in the winter (significant 20.3% reduction [P = .0008]). Reductions in the other seasons ranged between 8.6% and 12.0%. CONCLUSIONS: These post hoc analyses indicate that inhaled triple therapy with extrafine BDP/FF/G reduces seasonal peaks in moderate and severe exacerbations, and confirm the overall utility of adding long-acting muscarinic antagonist to ICS/long-acting ß2-agonist in the management of asthma.

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids.

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 µg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 µg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD. TRIAL REGISTRATION:  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Efficacy of budesonide/glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts.

BACKGROUND: In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. METHODS: KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 µg, GFF 14.4/10 µg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 µg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 µg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12-24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. RESULTS: Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population. CONCLUSIONS: In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001.

Efficacy and safety of single-inhaler extrafine triple therapy versus inhaled corticosteroid plus long-acting beta2 agonist in eastern Asian patients with COPD: the TRIVERSYTI randomised controlled trial.

BACKGROUND: A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. METHODS: TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint. RESULTS: Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup. CONCLUSIONS: In patients with COPD, FEV1 < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ).

Coagulation Effect of Sugammadex as Determined by Thromboelastography in a Randomized Controlled Study of Surgical Patients.

Introduction: Sugammadex has been shown to be associated with prolongation of prothrombin time and activated partial thromboplastin time. However, it is not known whether it could be associated with enhancing postoperative hypocoagulation. The objective of this study was to analyze the effect of 4 mg/kg of sugammadex on thromboelastography (TEG) parameters in surgical patients. Methods: After Institutional Review Board approval, a prospective double-blinded randomized controlled study was conducted between September 2016 and April 2017. Sixty adult patients scheduled for laparoscopic abdominal surgery were randomly allocated to receive either sugammadex 4 mg/kg (sugammadex group) or pyridostigmine 0.15 mg/kg in combination with glycopyrrolate 0.4 mg (control group) to reverse rocuronium-induced neuromuscular blockade at the completion of surgery. Blood samples were collected three time points; After the final suture of surgery (baseline) (T1), and at 10 min (T2) and 1 h (T3) after administration of the study drug. Whole blood was analyzed by TEG using TEG 5000 (Hemonetics Corp, Braintree, MA, USA). The primary endpoints were comparison of coagulation time (K, time to 20 mm clot amplitude), R (reaction time), alpha angle, and maximal amplitude (MA) between two groups. Results: Coagulation time was significantly prolonged in sugammadex group after 10 min of the study drug administration compared to control group (mean value 1.3 ± 0.4 vs. 1.5 ± 0.4, P = 0.03). However, R, alpha angle and MA value were not different between two groups. Conclusions: Sugammadex 4 mg/kg showed an increase in coagulation time in surgical patients. Physician should aware the potential enhancement of hypocoagulation by sugammadex in the setting of high risk of postoperative bleeding.

A new medication, a new toxidrome - A case report of anticholinergic wipe toxicity due to improper medication use.

We describe a case of a young female who presented to the emergency department with 4 days of progressive myopia, dry mouth, anhidrosis and urinary hesitancy due to overuse of a new topical anticholinergic wipes, glycopyrronium tosylate (GT). In the United States medication misuse accounts for nearly 10% of pediatric emergency visits with 65% of these visits considered to be preventable [1]. Being familiar with new medications and their side effect profiles can prevent unnecessary or harmful interventions.

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

BACKGROUND: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d. METHODS: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 µg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 µg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14. RESULTS: In total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed. CONCLUSION: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups. TRIAL REGISTRATION: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.

A randomized trial evaluating the safety profile of sugammadex in high surgical risk ASA physical class 3 or 4 participants.

BACKGROUND: The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest. METHODS: Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias. RESULTS: Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study. CONCLUSIONS: Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346057 .

Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials.

BACKGROUND: To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two studies that compared the single-inhaler extrafine combination of beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long-acting ß2 agonist), and glycopyrronium (G; long-acting muscarinic antagonist) with the combination of BDP with FF. METHODS: Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), and from 221 sites across 17 countries (TRIGGER). The sites were a mixture of secondary and tertiary care centres and specialised investigation units. Eligible patients were adults (aged 18-75 years) with uncontrolled asthma, a history of one or more exacerbations in the previous year, and previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting ß2 agonist. Enrolled patients were initially treated with BDP/FF (TRIMARAN: 100 µg BDP and 6 µg FF; TRIGGER: 200 µg BDP and 6 µg FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system with a balanced block randomisation scheme stratified by country. Patients, investigators, site staff, and sponsor staff were masked to BDP/FF/G and BDP/FF assignment. In TRIMARAN, patients were randomly assigned (1:1) to 52 weeks of BDP/FF/G (100 µg BDP, 6 µg FF, and 10 µg G) or BDP/FF (100 µg BDP and 6 µg FF), two inhalations twice daily. In TRIGGER, patients were randomly assigned (2:2:1) to 52 weeks of BDP/FF/G (200 µg BDP, 6 µg FF, and 10 µg G) or BDP/FF (200 BDP and 6 µg FF), both two inhalations twice daily, or open-label BDP/FF (200 µg BDP and 6 µg FF) two inhalations twice daily plus tiotropium 2·5 µg two inhalations once daily. Coprimary endpoints for both trials (BDP/FF/G vs BDP/FF) were pre-dose forced expiratory volume in 1 s (FEV1) at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment. These trials were registered with ClinicalTrials.gov, NCT02676076 (TRIMARAN), NCT02676089 (TRIGGER). FINDINGS: Between Feb 17, 2016, and May 17, 2018, 1155 patients in TRIMARAN were given BDP/FF/G (n=579) or BDP/FF (n=576). Between April 6, 2016, and May 28, 2018, 1437 patients in TRIGGER were given BDP/FF/G (n=573), BDP/FF (n=576), or BDP/FF plus tiotropium (n=288). Compared with the BDP/FF group, week 26 predose FEV1 improved in the BDP/FF/G group by 57 mL (95% CI 15-99; p=0·0080) in TRIMARAN and by 73 mL (26-120; p=0·0025) in TRIGGER, with reductions in the rate of moderate and severe exacerbations of 15% (rate ratio 0·85, 95% CI 0·73-0·99; p=0·033) in TRIMARAN and 12% (0·88, 0·75-1·03; p=0·11) in TRIGGER. Four patients had treatment-related serious adverse events, one in TRIMARAN in the BDP/FF/G group and three in TRIGGER-one in the BDP/FF/G and two in the BDP/FF group. Three patients in the BDP/FF/G group in TRIMARAN and two patients in TRIGGER-one in the BDP/FF/G group and one in the BDP/FF group-had adverse events leading to death. None of the deaths were considered as related to treatment. INTERPRETATION: In uncontrolled asthma, addition of a long-acting muscarinic antagonist to inhaled corticosteroid plus long-acting ß2-agonist therapy improves lung function and reduces exacerbations. FUNDING: Chiesi Farmaceutici.

COPD clinical control as a predictor of future exacerbations: concept validation in the SPARK study population.

The concept of chronic obstructive pulmonary disease (COPD) control has been proposed to guide treatment decisions in COPD. In this study, we aimed to validate the prospective value of this concept in the SPARK study population. Control was assessed based on COPD stability and impact. Patients with low impact and stability during weeks 1-12 were classified as controlled, and exacerbations were measured during a 52-week follow-up. Of the 2044 patients included a majority were non-controlled (80%), frequently due to high impact. During the follow-up, the rate of moderate/severe exacerbations was significantly lower in controlled patients (rate ratio, 0.56, 95% CI 0.48 to 0.65 p<0.0001) and time-to-first moderate/severe exacerbation was significantly delayed. This study demonstrated an association between control status and risk of exacerbations.

Glycopyrrolate/formoterol fumarate metered dose inhaler for maintenance-naïve patients with chronic obstructive pulmonary disease: a post-hoc analysis of the randomized PINNACLE trials.

BACKGROUND: Glycopyrrolate (GP)/formoterol fumarate (FF; GFF) metered dose inhaler is a fixed-dose combination dual bronchodilator for patients with chronic obstructive pulmonary disease (COPD); however, whether the efficacy in patients without current maintenance treatment is consistent with currently maintenance-treated patients is unclear. METHODS: Data from patients who were not maintenance-treated at screening (NMT) (n = 1943) and patients who were maintenance-treated at screening (MT) patients (n = 3040) receiving GFF, FF, GP, or placebo were pooled from the Phase III PINNACLE studies (NCT01854645, NCT01854658, NCT02343458) for post-hoc analysis. MT patients had received long-acting bronchodilators and/or inhaled corticosteroids in the 30 days prior to screening, and/or prior to randomization. NMT patients had received short-acting bronchodilators or no treatment. Outcomes included forced expiratory volume over 1 s (FEV1), clinically important deterioration (CID), rescue medication use, and safety. RESULTS: GFF provided significant lung function improvements at Week 24 versus placebo, GP, and FF for NMT patients, with pre-dose trough FEV1 treatment differences of 152 (117-188) mL, 73 (45-100) mL, and 56 (29-84) mL, respectively (least squares mean change from baseline versus comparators [95% CI]; all P < 0.0001). GFF reduced the risk of CID by 17-43% in NMT (P ≤ 0.0157) and 18-52% (P ≤ 0.0012) in MT patients compared with monotherapy and placebo, and reduced rescue medication use by 1.5 puffs/day over 24 weeks for both cohorts. Safety profiles for all cohorts were consistent with each other and the parent studies. CONCLUSIONS: NMT patients achieved better lung function with GFF versus monotherapy and placebo, without increased safety risk. Dual bronchodilator therapy may offer better outcomes than monotherapy for COPD patients when administered as first-line treatment.

Determinants of response to inhaled extrafine triple therapy in asthma: analyses of TRIMARAN and TRIGGER.

BACKGROUND: A number of single-inhaler triple therapies are being developed for asthma, including the extrafine formulation of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G). Given asthma is a heterogenous disease, we investigated whether the clinical response to the addition of the long-acting muscarinic antagonist component within inhaled triple therapy was impacted by a range of clinical characteristics. METHODS: These were pre-specified and post-hoc sub-group analyses of TRIMARAN and TRIGGER, which were double-blind, 52-week studies comparing medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with the respective BDP/FF strengths in adults with uncontrolled asthma and a history of ≥ 1 exacerbation. Co-primary endpoints were pre-dose forced expiratory volume in 1 s (FEV1) at Week 26 and the rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints: peak FEV1 at Week 26 and average morning peak expiratory flow over the first 26 weeks in each study, and severe exacerbation rate over 52 weeks (pooled data). RESULTS: Baseline clinical characteristics (pre-specified analyses) had no consistent effect on the lung function improvements with BDP/FF/G. For the exacerbation endpoints, sub-groups with higher reversibility gained greatest relative benefit from BDP/FF/G versus BDP/FF. In post-hoc analyses with patients sub-grouped by screening blood eosinophil values, in TRIMARAN the greatest relative effect of BDP/FF/G versus BDP/FF on the lung function endpoints was in the ≤ 300 cells/µL group; in TRIGGER, eosinophil levels did not markedly influence the relative efficacy of BDP/FF/G versus BDP/FF. Eosinophil levels did not influence relative efficacy on moderate-to-severe or severe exacerbations. CONCLUSION: Overall, the relative efficacy of extrafine BDP/FF/G versus BDP/FF was not influenced by a range of clinical characteristics. However, some patient sub-groups gained additional benefit from BDP/FF/G for certain endpoints. In particular, for exacerbations the relative efficacy of BDP/FF/G was greater in more reversible patients. Trial registration ClinicalTrials.gov: TRIMARAN, NCT02676076 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676076?term=NCT02676076&draw=2&rank=1 ,); TRIGGER, NCT02676089 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676089?term=NCT02676089&draw=2&rank=1 ).

Impact of baseline symptoms and health status on COPD exacerbations in the FLAME study.

BACKGROUND: COPD is a heterogeneous disease and patients may respond differently to therapies depending on baseline symptom burden. METHODS: This post-hoc analysis from the 52-week FLAME study investigated the impact of baseline symptom burden in terms of health status, dyspnoea, bronchitis status, eosinophil levels and smoking status on the subsequent risk of moderate or severe exacerbations. Health status was measured by St. George's Respiratory Questionnaire (SGRQ) score (higher ≥46.6 and lower < 46.6) and COPD Assessment Test (CAT) score (higher ≥17 and lower < 17); dyspnoea and bronchitis were assessed via an electronic diary (eDiary). Differential response to once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 µg versus twice-daily salmeterol/fluticasone (SFC) 50/500 µg was assessed. RESULTS: Data from 3354 patients was analysed. The risk of exacerbations was lower in patients who had less severe health impairment (rate ratio [RR] [95% CI]): SGRQ-C, (0.88 [0.78, 0.99]); CAT, 0.85 [0.75, 0.96]) and lower dyspnoea (0.79 [0.69, 0.90]) at baseline versus those with more severe health impairment and higher dyspnoea, respectively. Compared with SFC, IND/GLY led to better prevention of moderate-to-severe exacerbations in the majority of groups studied. CONCLUSION: Patients with more severe health status impairment and greater symptom burden at baseline subsequently experienced more exacerbations in the FLAME study. IND/GLY was overall more effective in preventing exacerbations versus SFC, regardless of baseline symptom burden. Our results suggest that future studies on novel exacerbation therapies should consider targeting patients with higher symptom burden at baseline. CLINICAL TRIAL IDENTIFIER: NCT01782326.