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A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting ?2-adrenergic agonist, in asthma; a Phase II, randomized study.

ABSTRACT: Long-acting ?2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 ?g, and duration of action compatible with once-daily dosing in patients with persistent, stable asthma.This was a Phase II, randomized, double-blind, double-dummy, crossover, placebo-controlled, dose-ranging study (ClinicalTrials.gov NCT01425801) in 62 patients with mild-to-moderate asthma who were also receiving an ICS. Patients received single doses of abediterol 0.313, 0.625, 1.25, or 2.5 ?g, salbutamol 400 ?g, or placebo in the morning. Spirometry was performed up to 36 h post-dose; safety and tolerability were assessed throughout the study. The primary endpoint was change from baseline in peak forced expiratory volume in 1 s (FEV1). Additional endpoints included trough FEV1, normalized area under the FEV1 curve (FEV1 AUC) up to 24 h post-dose, and peak and trough forced vital capacity (FVC).Abediterol produced dose-dependent improvements in peak FEV1 from baseline compared with placebo, from 0.274 (95% CI 0.221, 0.327) to 0.405 L (95% CI 0.353, 0.458) for abediterol 0.313 to 2.5 ?g, respectively (p?

SUBMITTER: Singh D

PROVIDER: S-EPMC4320624 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β2-adrenergic agonist, in asthma; a Phase II, randomized study.

Singh Dave D Pujol Helena H Ribera Anna A Seoane Beatriz B Massana Eric E Astbury Carol C Ruiz Sandrine S de Miquel Gonzalo G

BMC pulmonary medicine 20141114

<h4>Background</h4>Long-acting β2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 μg, and duration of action compatible with once-daily dosing in patients with persistent, stable asthm ...[more]

PMID: 25398689

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Project description:BackgroundAbediterol is a novel, once-daily long-acting β2-agonist in development for the treatment of chronic obstructive pulmonary disease (COPD) and asthma in combination with an anti-inflammatory agent. This Phase IIa, randomised, double-blind, crossover study investigated the bronchodilation, safety, tolerability and pharmacokinetics of abediterol in patients with moderate to severe COPD.MethodsSeventy patients (aged ≥40 years, Global initiative for chronic Obstructive Lung Disease Stage II/III) were randomised (1:1:1:1:1:1) to single doses of abediterol 0.625, 2.5, 5 or 10 μg, indacaterol 150 μg or placebo. Spirometry was performed up to 36 h post-dose. Pharmacokinetics were assessed in a subset of patients (N = 20). Safety and tolerability were evaluated throughout the study.ResultsAbediterol (all doses) significantly improved change from baseline in trough forced expiratory volume in 1 s (FEV1) compared with placebo (0.102, 0.203, 0.233 and 0.259 L for abediterol 0.625, 2.5, 5 and 10 μg, respectively; all p < 0.0001; primary endpoint). Abediterol 2.5, 5 and 10 μg significantly improved trough FEV1 compared with indacaterol 150 μg (0.092, 0.122 and 0.148 L, respectively; all p < 0.0001). Improvements in bronchodilation were maintained at all time points post-dose versus placebo (all abediterol doses) and from 15 or 30 min post-dose versus indacaterol 150 μg with abediterol 2.5, 5 and 10 μg (all p < 0.05). Abediterol had low systemic exposure; incidence of treatment-emergent adverse events was similar between treatment groups.ConclusionsAll doses of abediterol (0.625-10 μg) provided clinically and statistically significant, dose-dependent improvements in bronchodilation versus placebo, and abediterol 2.5, 5 and 10 μg gave significant improvements versus indacaterol. All doses of abediterol were safe and well tolerated in patients with COPD.Trial registrationClinicaltrials.gov NCT01425814 . Registered 29 August 2011.

Project description:Background and objectiveThere is presently no clear evidence on the effect of combined treatment for non-cystic fibrosis (non-CF) bronchiectasis with inhaled corticosteroid (ICS) and long-acting β2-adrenergic agonist (LABA). The objective of this study is to assess the efficacy and safety of salmeterol-fluticasone combined inhaled therapy for non-CF bronchiectasis with airflow limitation.MethodsAn observational study was performed in 120 non-CF bronchiectasis patients diagnosed by high-resolution computed tomography (HRCT) scanning of the chest. Patients received either routine therapy or salmeterol-fluticasone (100/500 μg daily) combined inhaled therapy on the basis of routine therapy. Clinical symptoms, health-related quality of life (HRQL), lung function, short-acting β2-adrenergic agonist (SABA) use, and safety were monitored throughout the study.ResultsOF the 120 subjects, 60 received combined inhaled therapy and 60 received routine therapy. Compared to the control group, the combined inhaled therapy group showed significant improvement in their clinical symptom scores (-2.21 vs. -0.31, P = 0.002) and a reduction in number of weekly SABA usage (-4.2 vs. 0.1, P < 0.01). In addition, patients in the inhaled therapy group achieved a significant improvement in HRQL based on mMRC (-1.51 vs. -0.31, P < 0.005) and SGRQ (-7.83 vs. -2.16, P < 0.01) scoring accompanied with no severe adverse events. There were fewer exacerbation frequencies in the combined inhaled therapy group over the 12 months of treatment compared to the control group (1 [0-2] vs. 2 [1-4], P = 0.017). Furthermore, stratified analysis indicated that combined inhaled therapy partially improve lung function for patients for whom it is severely impaired and those with pseudomonas aeruginosa isolated.ConclusionOur results show that salmeterol-fluticasone combined inhaled therapy should be effective and safe for non-CF bronchiectasis patients especially for those patients with poor lung function or pseudomonas aeruginosa isolated.

Project description:BackgroundOlodaterol is a novel, inhaled long-acting β2-agonist (LABA) with >24-hour duration of action investigated in asthma and chronic obstructive pulmonary disease.MethodsTwo multicentre studies examined the efficacy and safety of 4 weeks' once-daily (QD) olodaterol (2, 5, 10 and 20 μg, with background inhaled corticosteroids) in patients with asthma. One randomised, double-blind, parallel-group study (1222.6; 296 patients) administered treatment in the morning. Pulmonary function tests (PFTs) were performed pre-dose (trough) and ≤3 hours post-dose (weeks 1 and 2), and ≤6 hours post-dose after 4 weeks; primary end point was trough forced expiratory volume in 1 second (FEV1) response (change from baseline mean FEV1) after 4 weeks. A second randomised, double-blind, placebo- and active-controlled (formoterol 12 μg twice-daily) incomplete-block crossover study (1222.27; 198 patients) administered QD treatments in the evening. PFTs were performed over a 24-hour dosing interval after 4 weeks; primary end point was FEV1 area under the curve from 0-24 hours (AUC0-24) response (change from study baseline [mean FEV1] after 4 weeks).ResultsStudy 1222.6 showed a statistically significant increase in trough FEV1 response with olodaterol 20 μg (0.147 L; 95 % confidence interval [CI]: 0.059, 0.234; p = 0.001) versus placebo, with more limited efficacy and no evidence of dose response compared to placebo across the other olodaterol doses (2, 5 and 10 μg). Study 1222.27 demonstrated increases in FEV1 AUC0-24 responses at 4 weeks with all active treatments (p < 0.0001); adjusted mean (95 % CI) differences from placebo were 0.140 (0.097, 0.182), 0.182 (0.140, 0.224), 0.205 (0.163, 0.248) and 0.229 (0.186, 0.272) L for olodaterol 2, 5, 10 and 20 μg, respectively, and 0.169 (0.126, 0.211) for formoterol, providing evidence of increased efficacy with higher olodaterol dose. Olodaterol was generally well tolerated, with a few events associated with known sympathomimetic effects, mainly with 20 μg.ConclusionsThe LABA olodaterol has >24-hour duration of action. In patients with asthma, evidence of bronchodilator efficacy was demonstrated with statistically and clinically significant improvements in the primary end point of trough FEV1 response measured in clinics over placebo for the highest administered dose of 20 μg in Study 1222.6, and statistically and clinically significant improvements versus placebo in FEV1 AUC0-24 responses at 4 weeks for all doses tested in Study 1222.27, which also exhibited a dose response. Bronchodilator efficacy was seen over placebo for all olodaterol doses for morning and evening peak expiratory flow in both studies. All doses were well tolerated.Trial registrationsNCT00467740 (1222.6) and NCT01013753 (1222.27).

Project description:BackgroundRoflumilast, a once-daily, selective phosphodiesterase-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. The RE(2)SPOND study is examining whether roflumilast, when added to an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) fixed-dose combination (FDC), further reduces exacerbations. The methodology is described herein.MethodsIn this Phase IV, multicenter, double-blind, placebo-controlled, parallel-group trial, participants were randomized 1:1 (stratified by long-acting muscarinic antagonist use) to receive roflumilast or placebo, plus ICS/LABA FDC, for 52 weeks. Eligible participants had severe COPD associated with chronic bronchitis, had two or more moderate-severe exacerbations within 12 months, and were receiving ICS/LABA FDC for ≥3 months. The primary efficacy measure is the rate of moderate or severe COPD exacerbations per participant per year. The secondary efficacy outcomes include mean change in prebronchodilator forced expiratory volume in 1 second (FEV1) over 52 weeks, rate of severe exacerbations, and rate of moderate, severe, or antibiotic-treated exacerbations. Additional assessments include spirometry, rescue medication use, the COPD assessment test, daily symptoms using the EXACT-Respiratory symptoms (E-RS) questionnaire, all-cause and COPD-related hospitalizations, and safety and pharmacokinetic measures.ResultsAcross 17 countries, 2,354 participants were randomized from September 2011 to October 2014. Enrollment goal was met in October 2014, and study completion occurred in June 2016.ConclusionThis study will further characterize the effects of roflumilast added to ICS/LABA on exacerbation rates, lung function, and health of severe-very severe COPD participants at risk of further exacerbations. The results will determine the clinical benefits of roflumilast combined with standard-of-care inhaled COPD treatment.

Project description:BackgroundIn chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs-glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)-in patients with COPD.MethodsWe enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC).ResultsNo significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported.ConclusionsThe three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported. Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020).

Dataset Information

A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting ?2-adrenergic agonist, in asthma; a Phase II, randomized study.

Publications

A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β2-adrenergic agonist, in asthma; a Phase II, randomized study.

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