Dataset Information

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.

ABSTRACT: BACKGROUND:Long-acting muscarinic antagonist/long-acting ?2-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 ?g or 36/9.6 ?g), GP MDI 36 ?g BID, FF MDI 7.2 and 9.6 ?g BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 ?g BID or tiotropium DPI 18 ?g 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 ?g or 36/9.6 ?g 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 ?g was non-inferior to GFF MDI 72/9.6 ?g 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 ?g and 36/9.6 ?g 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.

SUBMITTER: Reisner C

PROVIDER: S-EPMC5216561 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.

Reisner Colin C Fabbri Leonardo M LM Kerwin Edward M EM Fogarty Charles C Spangenthal Selwyn S Rabe Klaus F KF Ferguson Gary T GT Martinez Fernando J FJ Donohue James F JF Darken Patrick P St Rose Earl E Orevillo Chad C Strom Shannon S Fischer Tracy T Golden Michael M Dwivedi Sarvajna S

Respiratory research 20170106 1

<h4>Background</h4>Long-acting muscarinic antagonist/long-acting β<sub>2</sub>-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).<h4>Methods</h4>This was a Phase IIb randomized, multicenter, placebo-controlled, doub ...[more]

PMID: 28061907

Similar Datasets

Project description:BackgroundLong-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).MethodsIn 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.ResultsIn 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.ConclusionsIn 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 registrationClinicalTrials.gov NCT02536508. Registered 27 August 2015.

Project description:BackgroundFor 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.MethodsPatients 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.ResultsA 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.ConclusionsAs 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 β2-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.

Project description:BackgroundTriple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD.MethodsThis phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs.ResultsThe mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64).ConclusionsRadiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD.Trial registrationClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Project description:Background:KRONOS, a Phase III, multicenter, randomized, double-blind study (NCT02497001) conducted in Canada, China, Japan, and the USA, assessed the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a triple fixed-dose combination therapy, relative to dual therapies in patients with moderate-to-very severe COPD. Here we present findings from the Japanese subgroup of KRONOS. Methods:Patients received BGF MDI 320/18/9.6μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12μg twice-daily for 24 weeks. The primary endpoint was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over Weeks 12-24. Symptoms, quality of life, exacerbations, and safety were also assessed. Results:In total, 416 Japanese patients (21.9% of the global KRONOS population) were randomized and treated with BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Nominally significant improvements in the change from baseline in morning pre-dose trough FEV1 over Weeks 12-24 were observed for BGF MDI vs GFF MDI (least squares mean [LSM] difference 37 mL, 95% confidence interval [CI] 3, 72; P=0.0337) and BFF MDI (67 mL; 95% CI 25, 109; P=0.0020). Treatment with BGF MDI led to a nominally significant reduction in the rate of moderate/severe exacerbations vs GFF MDI (rate ratio 0.40, 95% CI 0.19, 0.83; P=0.0142). Compared with dual therapies, numerical improvements were observed with BGF MDI for Transition Dyspnea Index focal score and the change from baseline in Evaluating Respiratory Symptoms in COPD total score (P≤0.3899). All treatments were generally well tolerated. Conclusion:BGF MDI nominally significantly improved lung function and numerically improved symptoms vs GFF MDI and BFF MDI. BGF MDI nominally significantly reduced exacerbations vs GFF MDI in Japanese patients with COPD. Efficacy and safety findings were generally comparable to those in the global KRONOS population.

Project description:BackgroundFunctional 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 β2-agonist (LABA), formoterol fumarate metered dose inhaler (FF MDI), on airway volume and resistance in patients with moderate-to-severe chronic obstructive pulmonary disease.MethodsPatients 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.ResultsA 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.ConclusionBoth 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 numberNCT02937584 The reviews of this paper are available via the supplemental material section.

Project description:Background:Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance. Patients and methods:In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 ?g) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography). Results:Twenty patients (46-78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both P<0.0001). Image-based airway volume (iVaw) and image-based airway resistance (iRaw), without adjusting for lobe volume, demonstrated corresponding findings to the co-primary endpoint, as lobe volumes did not change with either treatment. Approximately 48% of the delivered dose of glycopyrronium and formoterol fumarate was estimated to be deposited in the lungs. Compared with placebo, GFF MDI treatment improved post-dose FEV1 and IC (443 mL and 454 mL, respectively; both P<0.001) and reduced FRC and RV (13% and 22%, respectively; both P<0.0001). There were no significant safety findings. Conclusion:GFF MDI demonstrated significant, clinically meaningful benefits on FRI-based airway volume and resistance in patients with moderate-to-severe COPD. Benefits were associated with improvements in FEV1, IC, and hyperinflation. Clinical trial registration:ClinicalTrials.gov: NCT02643082.

Project description:BackgroundThis 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).MethodsThis 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.ResultsGP 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.ConclusionsThese 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 registrationClinicalTrials.gov NCT01566773 . Registered 27 March 2012.

Dataset Information

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.

Publications

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets