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A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study.

ABSTRACT: Two once-daily long-acting muscarinic antagonists (LAMAs) are currently available for the treatment of chronic obstructive pulmonary disease (COPD) - tiotropium and glycopyrronium. Previous studies have compared glycopyrronium with open-label tiotropium. In the GLOW5 study, we compare glycopyrronium with blinded tiotropium.In this blinded, double-dummy, parallel group, 12-week study, patients with moderate-to-severe COPD were randomized 1:1 to glycopyrronium 50 ?g once daily or tiotropium 18 ?g once daily. The primary objective was to demonstrate the non-inferiority of glycopyrronium versus blinded tiotropium with respect to trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment (non-inferiority margin: -50 mL). Secondary objectives were to evaluate glycopyrronium versus tiotropium for other spirometric outcomes, breathlessness (Transition Dyspnea Index; TDI), health status (St George's Respiratory Questionnaire; SGRQ), daily rescue medication use, COPD exacerbations and COPD symptoms over 12 weeks of treatment.657 patients were randomized (glycopyrronium: 327; tiotropium: 330); 96% (630 patients) completed the study. Least squares mean trough FEV1 for both glycopyrronium and tiotropium was 1.405 L at Week 12, meeting the criterion for non-inferiority (mean treatment difference: 0 mL, 95% CI: -32, 31 mL). Glycopyrronium demonstrated rapid bronchodilation following first dose on Day 1, with significantly higher FEV1 at all time points from 0-4 h post-dose versus tiotropium (all p < 0.001). FEV1 area under the curve from 0-4 h (AUC0-4h) post-dose with glycopyrronium was significantly superior to tiotropium on Day 1 (p < 0.001) and was comparable to tiotropium at Week 12. Glycopyrronium demonstrated comparable improvements to tiotropium in TDI focal score, SGRQ total score, rescue medication use and the rate of COPD exacerbations (all p = not significant). Patients on glycopyrronium also had a significantly lower total COPD symptom score versus patients on tiotropium after 12 weeks (p = 0.035). Adverse events were reported by a similar percentage of patients receiving glycopyrronium (40.4%) and tiotropium (40.6%).In patients with moderate-to-severe COPD, 12-week blinded treatment with once-daily glycopyrronium 50 ?g or tiotropium 18 ?g, provided similar efficacy and safety, with glycopyrronium having a faster onset of action on Day 1 versus tiotropium.

SUBMITTER: Chapman KR

PROVIDER: S-EPMC3907130 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study.

Chapman Kenneth R KR Beeh Kai-Michael KM Beier Jutta J Bateman Eric D ED D'Urzo Anthony A Nutbrown Robert R Henley Michelle M Chen Hungta H Overend Tim T D'Andrea Peter P

BMC pulmonary medicine 20140117

<h4>Background</h4>Two once-daily long-acting muscarinic antagonists (LAMAs) are currently available for the treatment of chronic obstructive pulmonary disease (COPD) - tiotropium and glycopyrronium. Previous studies have compared glycopyrronium with open-label tiotropium. In the GLOW5 study, we compare glycopyrronium with blinded tiotropium.<h4>Methods</h4>In this blinded, double-dummy, parallel group, 12-week study, patients with moderate-to-severe COPD were randomized 1:1 to glycopyrronium 50 ...[more]

PMID: 24438744

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Project description:BackgroundAddition of a second bronchodilator from a different pharmacological class may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) whose symptoms are insufficiently controlled by bronchodilator monotherapy. GLOW6 evaluated the efficacy and safety of once-daily coadministration of the long-acting β2-agonist indacaterol (IND) and the long-acting muscarinic antagonist glycopyrronium (GLY) versus IND alone in patients with moderate-to-severe COPD.Materials and methodsIn this randomized, double-blind, parallel group, placebo-controlled, 12-week study, patients were randomized 1:1 to IND 150 μg and GLY 50 μg daily (IND + GLY) or IND 150 μg daily and placebo (IND + PBO) (all delivered via separate Breezhaler® devices). The primary objective was to demonstrate the superiority of IND + GLY versus IND + PBO for trough forced expiratory volume in 1 second (FEV1) at week 12. Other end points included trough FEV1 at day 1, FEV1 area under the curve from 30 minutes to 4 hours (AUC30min-4h), peak FEV1, inspiratory capacity and trough forced vital capacity (FVC) at day 1 and week 12, and transition dyspnea index (TDI) focal score, COPD symptoms, and rescue medication use over 12 weeks.ResultsA total of 449 patients were randomized (IND + GLY, 226; IND + PBO, 223); 94% completed the study. On day 1 and at week 12, IND + GLY significantly improved trough FEV1 versus IND + PBO, with treatment differences of 74 mL (95% CI 46-101 mL) and 64 mL (95% CI 28-99 mL), respectively (both P<0.001). IND + GLY significantly improved postdose peak FEV1, FEV1 AUC30min-4h, and trough FVC at day 1 and week 12 versus IND + PBO (all P<0.01). TDI focal score and COPD symptoms (percentage of days able to perform usual daily activities and change from baseline in mean daytime respiratory score) were significantly improved with IND + GLY versus IND + PBO (P<0.05). The incidence of adverse events was similar for the two treatment groups.ConclusionIn patients with moderate-to-severe COPD, once-daily coadministration of IND and GLY provides significant and sustained improvement in bronchodilation versus IND alone from day 1, with significant improvements in patient-centered outcomes.

Project description:Bronchodilation with muscarinic antagonists, β2-agonists, and inhaled corticosteroids remains the foundation of pharmaceutical treatment for patients with stable COPD. These drugs are delivered from a variety of devices, including dry powder inhalers, pressurized metered-dose inhalers, soft-mist inhalers, or nebulizers. Nebulized delivery is often preferable in patients who are elderly, are cognitively impaired, are unable to generate sufficient inspiratory force to use their inhaler, have difficulty coordinating hand-breath activity, are too dyspneic to hold their breath for a sufficient time, and/or may be acutely ill. Revefenacin, a once-daily long-acting muscarinic antagonist for nebulization recently approved by the US FDA for the treatment of patients with COPD, was discovered and developed using "duration and lung selectivity-by-design." This strategy selected a molecule with a high lung-selective index to maximize bronchodilation and limit systemic anti-muscarinic side effects. In early-phase clinical studies, revefenacin for nebulization led to a rapid onset of bronchodilation that was sustained for 24 hrs in patients with moderate to severe COPD. Revefenacin also demonstrated minimal systemic exposure and good tolerability in these studies. Statistically and clinically significant improvements in lung function (ie, peak and/or trough FEV1) relative to placebo were observed with revefenacin in Phase III clinical trials of up to 3 months in patients with moderate to very severe COPD. Revefenacin was well tolerated in Phase III clinical trials with a low incidence of systemic antimuscarinic adverse events, which is consistent with its lung-selective design. There was no evidence of an increased risk of major cardiovascular events. Patient-reported outcome data from clinical trials indicated statistically significant improvements in several disease-specific measures. Revefenacin 175 μg for nebulization provides an effective once-daily treatment option for patients with moderate to very severe COPD who require or prefer nebulized therapy.

Project description:INTRODUCTION:Comparative data on the efficacies of long-acting muscarinic antagonist (LAMA) and long-acting ?2-agonist (LABA) combinations for the treatment of moderate-to-very-severe chronic obstructive pulmonary disease (COPD) are limited. The aim of this Bayesian network meta-analysis (NMA) is to assess the relative efficacies of available open combinations (delivered via separate inhalers) and fixed-dose combinations (FDCs, delivered via a single inhaler). METHODS:We conducted a systematic literature review with the aim of identifying randomized controlled trials (RCTs) of ?8-week duration in adults aged ?40 years with COPD that compared LAMA + LABA combinations with each other, with tiotropium (TIO), or with placebo. Data on changes from baseline in trough forced expiratory volume in 1 s (FEV1) and on St George's Respiratory Questionnaire (SGRQ) total score, the Transition Dyspnea Index (TDI) focal score, and rescue medication use at 12 and 24 weeks were extracted from these RCTs and analyzed using a NMA in a Bayesian framework. RESULTS:Data from 44 RCTs were included in the NMA. All FDCs showed improvements relative to placebo in terms of trough FEV1, SGRQ total score, and TDI focal score above clinically relevant thresholds, with the exception of TIO/olodaterol and aclidinium/formoterol, both of which failed to show clinically relevant improvements in SGRQ score at 24 weeks. All FDCs demonstrated reduced rescue medication use versus placebo. Open combinations demonstrated improved efficacy in all outcomes versus placebo, but these improvements did not consistently exceed clinically relevant thresholds for SGRQ and TDI scores. All once-daily FDCs showed improved efficacy versus TIO, but improvements were less consistently observed versus TIO with open dual combinations and combinations containing formoterol or salmeterol administered twice daily. Relative probabilities of improvement between FDCs highlighted potential between-class differences for trough FEV1 but suggested little potential for differences in patient-reported outcomes. CONCLUSION:LAMA + LABA combinations generally showed improved outcomes versus placebo and TIO. FDCs appeared to perform better than open dual combinations. A potential effectiveness gradient was observed between FDCs for objectively assessed functional outcomes, although further prospective trials are required to confirm these findings. FUNDING:GSK.

Project description:BackgroundRandomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative efficacy of tiotropium 18 µg once-daily (OD) and newer agents (aclidinium 400 µg twice-daily, glycopyrronium 50 µg OD, and umeclidinium 62.5 µg OD).MethodsA systematic literature review identified randomized, controlled trials of adult COPD patients receiving LAMAs. A NMA within a Bayesian framework examined change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnea index focal score, St George's Respiratory Questionnaire score, and rescue medication use.ResultsTwenty-four studies (n=21,311) compared LAMAs with placebo/each other. Aclidinium, glycopyrronium, tiotropium, and umeclidinium, respectively, demonstrated favorable results versus placebo, for change from baseline (95% credible interval) in 12-week trough FEV1 (primary endpoint: 101.40 mL [77.06-125.60]; 117.20 mL [104.50-129.90]; 114.10 mL [103.10-125.20]; 136.70 mL [104.20-169.20]); 24-week trough FEV1 (128.10 mL [84.10-172.00]; 135.80 mL [123.10-148.30]; 106.40 mL [95.45-117.30]; 115.00 mL [74.51-155.30]); 24-week St George's Respiratory Questionnaire score (-4.60 [-6.76 to -2.54]; -3.14 [-3.83 to -2.45]; -2.43 [-2.92 to -1.93]; -4.69 [-7.05 to -2.31]); 24-week transitional dyspnea index score (1.00 [0.41-1.59]; 1.01 [0.79-1.22]; 0.82 [0.62-1.02]; 1.00 [0.49-1.51]); and 24-week rescue medication use (data not available; -0.41 puffs/day [-0.62 to -0.20]; -0.52 puffs/day [-0.74 to -0.30]; -0.30 puffs/day [-0.81 to 0.21]). For 12-week trough FEV1, differences in change from baseline (95% credible interval) were -12.8 mL (-39.39 to 13.93), aclidinium versus tiotropium; 3.08 mL (-7.58 to 13.69), glycopyrronium versus tiotropium; 22.58 mL (-11.58 to 56.97), umeclidinium versus tiotropium; 15.90 mL (-11.60 to 43.15), glycopyrronium versus aclidinium; 35.40 mL (-5.06 to 76.07), umeclidinium versus aclidinium; and 19.50 mL (-15.30 to 54.38), umeclidinium versus glycopyrronium. Limitations included inhaler-related factors and safety; longer-term outcomes were not considered.ConclusionThe new LAMAs studied had at least comparable efficacy to tiotropium, the established class standard. Choice should depend on physician's and patient's preference.

Dataset Information

A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study.

Publications

A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study.

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