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Background: For patients who experience COPD exacerbations on LAMA/LABA, GOLD recommends step-up to ICS/LAMA/LABA triple therapy for those with blood eosinophil counts (EOS) ≥100 cells/mm3. In the 52-week ETHOS trial (NCT02465567), triple therapy with BGF MDI at two ICS dose levels reduced the rate of moderate/severe COPD exacerbations vs dual therapies. Objective: To assess exacerbation rates in patients with EOS Methods: Patients with moderate-to-very severe COPD and ≥1 moderate/severe exacerbation in the prior year were randomised to BGF MDI 320/14.4/10µg or 160/14.4/10µg, glycopyrronium/formoterol (GFF) MDI 14.4/10µg or budesonide/formoterol (BFF) MDI 320/10µg (all treatments administered twice-daily in a single Aerosphere inhaler). Results: In the modified ITT population (n=8509), 82.6% of patients had EOS ≥100. In these patients, both doses of BGF MDI reduced moderate/severe exacerbations vs GFF MDI (by 28–29%, both p Conclusions: BGF MDI reduced exacerbations vs GFF MDI and BFF MDI in patients with EOS ≥100 but only vs BFF MDI in EOS

Background: In the 52-week ETHOS trial (NCT02465567), the triple fixed-dose combination BGF MDI containing 320 µg or 160 µg budesonide reduced the rate of moderate/severe COPD exacerbations vs dual therapies. Objective: To assess exacerbation rates by month of treatment in the ETHOS trial. Methods: Patients with moderate-to-very severe COPD and ≥1 moderate/severe exacerbation in the prior year were randomised to BGF MDI 320/14.4/10 µg or 160/14.4/10 µg, glycopyrronium/formoterol (GFF) MDI 14.4/10 µg or budesonide/formoterol (BFF) MDI 320/10 µg, each administered twice-daily via a single Aerosphere inhaler. In a pre-specified analysis, annualised exacerbation rates were assessed in consecutive 4-week intervals using generalised estimating equation modelling. Results: In the modified ITT population (n=8509), 56.5% had experienced ≥2 moderate/severe exacerbations in the previous year; 80.5% were using ICS at screening. Within each treatment group, exacerbation rates by monthly interval were generally consistent across the study period. The rate ratios were Conclusions: Reductions in COPD exacerbation rates with BGF MDI 320/14.4/10 µg (ICS/LAMA/LABA) vs LAMA/LABA were observed throughout the study and not only during the early weeks of treatment.

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.

Colin Reisner,1,2 James Pearle,3 Edward M Kerwin,4 Earl St Rose,1 Patrick Darken1 1Pearl – a member of the AstraZeneca Group, Morristown, NJ, USA; 2AstraZeneca, Gaithersburg, MD, USA; 3California Research Medical Group, Inc., Fullerton, CA, USA; 4Clinical Research Institute of Southern Oregon, Medford, OR, USA 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, 9/9.6μg) 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 7days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0–12) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 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 FEV1 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 endpoint, 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. Keywords: bronchodilator, chronic obstructive pulmonary disease, co-suspension delivery technology, fixed-dose combination, LAMA/LABA, long-acting β2-agonist, long-acting muscarinic antagonist

Edward M Kerwin,1 Thomas M Siler,2 Samir Arora,3 Patrick Darken,4 Earl St Rose,4 Colin Reisner4,5 1Clinical Research Institute of Southern Oregon, Medford, OR, USA; 2Midwest Chest Consultants, St Charles, MO, USA; 3Aventiv Research, Columbus, OH, USA; 4Pearl – a member of the AstraZeneca Group, Morristown, NJ, USA; 5AstraZeneca, Gaithersburg, MD, USA Purpose: This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting β2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD. Materials and methods: In this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 μg and FF MDI 9.6 μg, and two of either BFF MDI 160/9.6 μg, BFF MDI 80/9.6 μg, or BD MDI 320 μg twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29. Results: Overall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 μg (least squares mean differences 186–221 mL; all p

Yasushi Fukushima,1 Yuji Nakatani,2 Yumiko Ide,3 Hisakuni Sekino,4 Earl St Rose,5 Shahid Siddiqui,6 Andrea Maes,5 Colin Reisner5,6 1Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 2Department of Internal Medicine, Nakatani Hospital, Hyogo, Japan; 3Department of Internal Medicine, Tokyo Center Clinic, Tokyo, Japan; 4Department of Internal Medicine, Sekino Hospital, Tokyo, Japan; 5Pearl – a member of the AstraZeneca Group, Morristown, NJ, USA; 6AstraZeneca, Gaithersburg, MD, USA 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 (FEV1) on Day 8. Secondary endpoints included FEV1 area under the curve from 0 to 2 hours (AUC0–2) and peak change from baseline in FEV1 on Days 1 and 8 and forced vital capacity AUC0–2 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 FEV1 on Day 8 compared with placebo MDI (least squares mean differences 108–131 mL; all p

Background Single inhaler triple therapies providing an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting β2-agonist (ICS/LAMA/LABAs) are an emerging treatment option for chronic obstructive pulmonary disease (COPD). Nevertheless, questions remain regarding the optimal patient population for triple therapy as well as the benefit:risk ratio of ICS treatment. Methods ETHOS is an ongoing, randomized, double-blind, multicenter, parallel-group, 52-week study in symptomatic patients with moderate-to-very severe COPD and a history of exacerbation(s) in the previous year. Two doses of single inhaler triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI 320/18/9.6 μg and 160/18/9.6 μg) will be compared to glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg and budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, all formulated using co-suspension delivery technology. Outcomes include the rate of moderate/severe (primary endpoint) and severe COPD exacerbations, symptoms, quality of life, and all-cause mortality. Sub-studies will assess lung function and cardiovascular safety. Study population From June 2015–July 2018, 16,044 patients were screened and 8572 were randomized. Preliminary baseline demographics show that 55.9% of patients had experienced ≥2 moderate/severe exacerbations in the previous year, 79.1% were receiving an ICS-containing treatment at study entry, and 59.9% had blood eosinophil counts ≥150 cells/mm3. Conclusions ETHOS will provide data on exacerbations, patient-reported outcomes, mortality, and safety in 8572 patients with moderate-to-very severe COPD receiving triple and dual fixed-dose combinations. For the first time, ICS/LAMA/LABA triple therapy with two different doses of ICS will be compared to dual ICS/LABA and LAMA/LABA therapies. Clinical trial registration number NCT02465567.

Background This study formed part of the dose selection for a glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination formulated using novel Co-Suspension™ Delivery Technology and delivered via a metered dose inhaler (GFF MDI). The study aimed to confirm the optimal dose of GP to formulate with FF 9.6 μg in the fixed-dose combination product, GFF MDI. Methods This multicenter, randomized, double-blind, chronic-dosing, balanced incomplete block, crossover study (NCT01587079) compared five doses of GFF MDI (18/9.6, 9/9.6, 4.6/9.6, 2.4/9.6 and 1.2/9.6 μg, twice daily [BID]) with its monocomponents FF MDI 9.6 μg and GP MDI 18 μg (both BID) and open-label tiotropium (18 μg once daily) as the active control. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV 1 AUC 0–12 ) on Day 7. Results In total, 159 patients were randomized to treatment and 132 patients (52.2% male, mean age 62.8 years) were included in the intent-to-treat population. All doses of GFF MDI (except 1.2/9.6 μg) resulted in statistically significant improvements in FEV 1 AUC 0–12 versus monocomponents and open-label tiotropium. GFF MDI 18/9.6 μg consistently showing the greatest improvement over monocomponents and open-label tiotropium. Adverse events for each GFF MDI dose were similar versus GP MDI 18 μg, FF MDI 9.6 μg and open-label tiotropium. Conclusions These findings further support selection of GP 18 μg as the optimal dose to combine with FF MDI 9.6 μg for advancement into Phase III clinical trials of GFF MDI.

This is the first study of the inhaled corticosteroid, budesonide, delivered by metered-dose inhaler (BD MDI) using innovative co-suspension delivery technology in adults with asthma.To characterize the effects of BD delivered by MDI on lung function and safety.Randomized, double-blind, 4-week cross-over, placebo-controlled, phase IIb study of adults (18-65 years of age) with mild-to-moderate persistent asthma. The subjects received twice-daily BD MDI 320 μg, 160 μg, and placebo MDI, and either BD MDI 80 μg or 40 μg. The primary endpoint was change from baseline in morning trough forced expiratory volume in 1 second (FEV1) at the end of the treatment period (EOT). Secondary endpoints included change from baseline in morning and evening predose peak expiratory flow rate (PEFR), rescue medication use, and Asthma Control Questionnaire 5-question version (ACQ-5) score. Safety was also assessed.A total of 147 subjects were randomized. All doses of BD MDI improved morning trough FEV1 at EOT, and morning and evening predose PEFR in the last treatment week versus placebo (all p0.01), with improvements in trough FEV1 exceeding 100 mL for BD MDI 320 μg, and 160 μg only. Compared with placebo, all BD MDI doses reduced rescue medication use in the last week of treatment (p0.01) and improved ACQ-5 scores at EOT (all p0.01). All treatments were well tolerated.Analysis of the data demonstrated greater efficacy improvements for the higher doses of BD MDI (320 μg and 160 μg), with similar adverse event profiles compared with the lower doses. Hence, BD MDI 320 μg and 160 μg warrant further evaluation in subjects with persistent asthma.Clinical trial NCT02105012,ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov"www.clinicaltrials.gov/ext-link.

Background Long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies. Methods In this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h (AUC0–12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study. Results All GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p

The budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) is an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination formulated with innovative co-suspension delivery technology that is in clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, Phase I, single-dose, six-treatment, four-period, crossover study (NCT01980615) examined the pharmacokinetic (PK) and safety profile of three doses of BGF MDI (320/14.4/10 μg [equivalent to budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 μg], 160/14.4/10 μg and 80/14.4/10 μg), two doses of a budesonide/formoterol fumarate dihydrate fixed-dose combination (BUD/FORM MDI 320/9 μg and 160/9 μg; not using co-suspension delivery technology) and a glycopyrronium/formoterol fumarate dihydrate co-suspension delivery technology MDI (GFF MDI 14.4/10 μg) in healthy volunteers (18-45 years of age). PK parameters included area under the plasma concentration-time curve from 0 to 12 h (AUC0-12), AUC up to the last measurable concentration (AUC0-t), maximum plasma concentration (Cmax) and time to maximum plasma concentration (tmax). Safety was monitored throughout the study. Of 84 subjects randomized, 76 completed the study. BGF MDI 320/14.4/10 μg was bioequivalent to BUD/FORM MDI 320/9 μg for budesonide for Cmax, AUC0-12 and AUC0-t (primary objective). Dose proportionality was observed for the budesonide component between BGF MDI 80/14.4/10 μg and BGF MDI 160/14.4/10 μg, and between BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg. Systemic exposure to glycopyrronium and formoterol after BGF MDI 320/14.4/10 μg treatment was similar to GFF MDI 14.4/10 μg. The rate of adverse events was 3.7-17.9% across treatments without any serious adverse events. In conclusion, BGF MDI 320/14.4/10 μg had a similar budesonide PK profile to BUD/FORM MDI 320/9 μg. No PK drug-drug interactions were observed when budesonide was added to glycopyrronium and formoterol fumarate dihydrate. These data support the use of budesonide 320 μg and 160 μg in future clinical trials of BGF MDI in COPD.

Background Long-acting muscarinic antagonist/long-acting β2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). Methods This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD (NCT01085045). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0–12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety. Results GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV1 AUC0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. Conclusions GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. Trial registration ClinicalTrials.gov NCT01085045. Registered 9 March 2010. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0491-8) contains supplementary material, which is available to authorized users.

Background Symptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily. Methods Patients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks’ treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0–24). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity. Results GFF MDI treatment significantly increased FEV1AUC0–24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0–12 and 12–24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12–24 compared to 0–12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (−0.84 [p15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings. Conclusions GFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI. Trial registration Pearl Therapeutics, Inc.; www.clinicaltrials.gov ; NCT02347072 and NCT02347085 . Registered 21 January 2015.

Long-acting muscarinic antagonist/long-acting β2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045 ). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0–12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety. GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV1 AUC0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. ClinicalTrials.gov NCT01085045 . Registered 9 March 2010.

Background This study forms part of the first complete characterization of the dose–response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 μg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 μg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0–12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed. Results GP MDI 18, 9, 4.6, and 2.4 μg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0–12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 μg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings. Conclusions These efficacy and safety results support GP MDI 18 μg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD. Trial registration ClinicalTrials.gov NCT01566773. Registered 27 March 2012. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0426-4) contains supplementary material, which is available to authorized users.

Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers. In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 μg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 μg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1). All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P

Rationale: This first-in-human study provided safety and pharmacokinetic (PK) data on a novel fixed dose combination of Glycopyrrolate and Formoterol Fumarate metered dose inhaler (MDI). Pearl’s novel porous particle based suspension technology allows better targeting of drugs to the airways via pressurized metered dose inhaler (MDI), and enables the development of combination products with improved physical stability, content uniformity, and aerodynamic size distribution similarity across the combination drug components. The objective of this study was to provide safety and PK evidence in support of further clinical studies in patients with COPD. Methods: Study PT0030901 was a randomized, double-blind, single-dose, 4-period crossover, single-center study in healthy subjects that evaluated a single administration of 4 inhaled treatments: glycopyrrolate 72 μg (GP), formoterol fumarate 9.6 μg (FF), the fixed combination GP/FF from a single MDI, and the loose combination of GP + FF administered from two separate MDIs. At each treatment visit, subjects were assessed for 12 hours after dosing. There was a minimum 7 day washout period between treatments. Evaluations included adverse events (AEs), dry mouth and tremor assessments, hematology, clinical chemistry, vital signs, 12-lead electrocardiograms (ECG), spirometry, physical examinations, and PK parameters. Results: Sixteen subjects (11 females, 5 males), average age 27 years (range 19 to 47), were enrolled with 13 subjects completing all treatment periods. No important safety trends or signals were noted for GP/FF MDI fixed dose combination in terms of AEs, changes in serum potassium or other laboratory values, vital signs, ECGs, or spirometry parameters. Conclusions: The novel GP/FF MDI fixed dose combination was safe and well-tolerated, with a safety profile similar to that observed with the components administered individually or at the same time as a loose combination. These safety findings support further evaluation of GP/FF MDI in patients with COPD.

SummaryBackgroundFormoterol fumarate (FF) is a well-established long-acting β2-agonist. This represents the first clinical study of FF in a metered-dose inhaler (FF MDI) based on proprietary lipid-based porous-particle engineering technology.MethodsIn this randomized, double-blind, 5-period, crossover study (NCT00880490), subjects received 2.4, 4.8, and 9.6 μg of FF MDI, open-label Foradil® Aerolizer® (FA) 12 μg, and placebo. Spirometry was performed at baseline, 15 and 30 min, and 1, 2, 4, 6, 8, 10, 11.5, and 12 h post-dose.ResultsThirty-four subjects were enrolled. Improvement in forced expiratory volume in 1 s (FEV1) was similar between FF MDI 9.6 μg and FA. Change in FEV1 area under the curve for 0–12 h (AUC0–12) for each FF MDI dose demonstrated superior efficacy versus placebo (P