Efficacy of Nebulized Glycopyrrolate on Lung Hyperinflation in Patients with COPD.

INTRODUCTION: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with activity limitation, impaired cardiac output, and mortality. Several studies have demonstrated that long-acting muscarinic antagonists (LAMAs) delivered by dry powder inhalers can promote lung deflation; however, the potential of nebulized LAMAs on improving hyperinflation in COPD is currently unknown. METHODS: This single-center, randomized, double-blind, two-way crossover study (NCT04155047) evaluated the efficacy of a single dose of nebulized LAMA [glycopyrrolate (GLY) 25 µg] versus placebo in patients with COPD and lung hyperinflation. Patients with moderate-to-severe COPD and a residual volume (RV) ≥ 130% of predicted normal were included. The primary endpoint was changed from baseline in RV at 6 h post-treatment. Other endpoints included changes from baseline in spirometric and plethysmographic measures up to 6 h post-treatment. RESULTS: A total of 22 patients (mean pre-bronchodilator RV, 153.7% of predicted normal) were included. The primary objective of the study was not met; the placebo-adjusted least squares (LS) mean [95% confidence interval (CI) change from baseline in RV with GLY at 6 h post-treatment was - 0.323 l (- 0.711 to 0.066); p = 0.0987]. A post hoc evaluation of the primary analysis was conducted after excluding a single statistical outlier; substantial improvements in RV with GLY compared with placebo was observed after exclusion of this outlier [placebo-adjusted LS mean change from baseline (95% CI) in RV was - 0.446 l (- 0.741 to - 0.150)]. Improvements from baseline were also observed with GLY compared with placebo in spirometric and plethysmographic measures up to 6 h post-treatment. GLY was generally safe, and no new safety signals were detected. CONCLUSIONS: This is the first study to evaluate the effect of nebulized GLY on lung deflation. Nebulized GLY resulted in marked improvements in RV up to 6 h post-treatment, compared with placebo. Improvements were also observed with GLY in spirometric and plethysmographic parameters of lung function. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04155047.

A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II.

PURPOSE: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. METHODS: Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. RESULTS: No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. CONCLUSIONS: These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.

The safety and efficacy of arformoterol and formoterol in COPD.

This study evaluated the safety and efficacy of arformoterol and formoterol over 6-months in subjects with COPD. In a multi-center, 6-month randomized, double-blind, double-dummy trial, subjects with COPD (mean FEV(1) 1.21 L, approximately 41.0% predicted) were randomized to receive either nebulized arformoterol (15 microg BID [n = 149][ARF 15], 25 microg BID [n = 147][ARF 25]), or racemic formoterol (12 microg BID [n = 147][FORM]) delivered by DPI. The proportion of subjects with any post-treatment adverse event for ARF 15, ARF 25 microg, and FORM was 67.8%, 76.2% and 66.7%, respectively, and those with at least one COPD exacerbation was 32.2%, 30.6%, and 22.4%, respectively. Pulmonary function improved for all treatment groups and was maintained throughout the study. Mean change from baseline at 6-months for ARF 15, ARF 25 and FORM in peak FEV(1) was 0.30L, and 0.34L, and 0.26L, respectively, in 24-hour trough FEV(1) was, 0.10L, 0.14L, and 0.09L, and in inspiratory capacity was, 0.20L, 0.37L, and 0.23L. Dyspnea, (mean Transition Dypsnea Index (TDI) focal score) improved in all treatment arms (ARF 15: 1.4, ARF 25: 1.5, and FORM: 1.4) at 6 months, as did rescue short-acting beta(2)-agonists use (mean range: -1.1 to -1.3 actuations/day) and ipratropium bromide (mean range: -0.3 to -0.8 actuations/day). Health status, measured by St George's Respiratory Questionnaire, improved from baseline at 6-months in all treatment groups (mean change: -3.7 to -6.8). In this 6-month study, arformoterol and formoterol were well-tolerated, and their use was associated with improvement in pulmonary function and health status in subjects with COPD with no apparent development of tolerance.

Effect of nebulized arformoterol on airway function in COPD: results from two randomized trials.

RATIONALE: Arformoterol, a single isomer long-acting beta(2)-agonist, was developed as an inhalation solution for the maintenance treatment of bronchoconstriction in COPD. METHODS: The pulmonary function efficacy of nebulized arformoterol (15 micro g BID, 25 micro g BID, 50 micro g QD) and salmeterol MDI (42 micro g BID) versus placebo was assessed in 1456 subjects (mean FEV(1) 1.2L, mean predicted 41%). Data were pooled from 2 identical, 12-week, double-blind, randomized trials. The percent change in trough FEV(1), percent change in FEV(1) average AUC((0 - 12 hrs)) and peak percent change FEV(1) from predose were analyzed. RESULTS: Improvement in trough FEV(1) averaged over 12 weeks was greater for arformoterol and salmeterol versus placebo (mean differences from placebo [95% CI] arformoterol-15 micro g BID: 11.4% [8.4, 14.3]; 25 micro g BID: 15.4% [12.2, 18.6]; 50 micro g QD: 10.9% [7.9, 13.9]); salmeterol: (11.6% [8.8, 14.4]). Greater improvements versus placebo occurred after the first dose (mean differences between arformoterol and placebo for trough FEV(1): 13-19%; FEV(1) AUC((0 - 12 hrs)): 19-24%; peak percent change: 20-25%) and at week 12 (trough FEV(1): 10-13%; FEV(1) AUC((0 - 12 hrs)): 6-13%; peak percent change: 7-14%); all 95% CIs excluded zero. Increases in FEV(1) AUC((0 - 12 hrs)) and peak percent change were greater for arformoterol than for salmeterol (95% CIs excluded zero). After 12 weeks, 78-87% of arformoterol subjects had > or = 10% increases in FEV(1) from pre-dose (56% salmeterol, 44% placebo); the median time to response was 3-13 minutes (142 minutes salmeterol). CONCLUSIONS: In these trials, COPD subjects administered nebulized arformoterol demonstrated significant and sustained improvement in lung function over 12 weeks.

Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial.

OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting beta(2)-adrenergic agonist that is the [R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. RESULTS: A total of 717 patients received study medication. The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV(1)) was 1.2 L (41% predicted). Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P