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Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD.

ABSTRACT: Background:Batefenterol is a novel bifunctional muscarinic antagonist ?2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development. Patients and methods:Patients aged ?40 years with COPD and FEV1 ?30% and ?70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0-6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose-response modeling, respectively, on day 42. Results:In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ?150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed. Conclusion:Batefenterol 300 µg may represent the optimal dose for Phase III studies.

SUBMITTER: Crim C

PROVIDER: S-EPMC6413745 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:BackgroundThree 52-week studies in COPD have assessed the efficacy and safety of single-inhaler extrafine formulation triple therapy combining beclomethasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) delivered via pressurized metered-dose inhaler (pMDI). BDP/FF/G is now being developed for delivery via multi-dose dry-powder inhaler (DPI; NEXThaler). This study aimed to demonstrate non-inferiority of BDP/FF/G DPI vs pMDI for lung function.MethodsMulticenter, randomized, double-blind, double-dummy, active-controlled, three-way cross-over study in patients with COPD and post-bronchodilator forced expiratory volume in 1 second (FEV1) 30-80% predicted. Patients received BDP/FF/G 100/6/10µg via DPI and pMDI, and BDP/FF 100/6µg via pMDI, all two inhalations twice daily for four weeks, with treatments separated by two-week washout. The two co-primary objectives were to demonstrate non-inferiority between the two BDP/FF/G formulations for FEV1 area under the curve between 0 and 12 hours post-dose (AUC0-12h) normalized by time and trough FEV1 at 24 hours, both on Day 28. EudraCT 2017-004405-41.ResultsOf 449 patients screened, 366 were randomized, with 342 (93.4%) completing all three treatment periods. The primary objectives were met, with changes from baseline in FEV1 AUC0-12h and trough FEV1 on Day 28 similar for the two BDP/FF/G formulations, and the confidence intervals for the difference lying entirely within the pre-specified non-inferiority criterion (-50mL): -20 (-35, -6) mL and 3 (-15, 20) mL for AUC0-12h and trough FEV1, respectively. BDP/FF/G pMDI and DPI were statistically superior to BDP/FF for these endpoints (p<0.001). A similar proportion of patients experienced adverse events with each treatment (15.5%, 18.7% and 15.4% with BDP/FF/G DPI and pMDI, and BDP/FF, respectively); the majority were mild or moderate, with few related to treatment.ConclusionExtrafine BDP/FF/G DPI and pMDI demonstrated similar efficacy and safety in patients with COPD, supporting the DPI formulation as a valid alternative.

Project description:BackgroundTo evaluate whether patients of varying ages and lung function with asthma or those with chronic obstructive pulmonary disease (COPD) can achieve sufficient inspiratory flows for effective use of the fixed-dose combination of salmeterol-fluticasone propionate and budesonide-formoterol dispensed with the Easyhaler® (EH) device-metered, multi-dose dry powder inhaler (DPI).MethodsA pooled analysis of two randomized, multicenter, crossover, open-label studies (NCT01424137; NCT009849061) was conducted to characterize inspiratory flow parameters across the EH, Seretide Diskus (DI) and Symbicort Turbuhaler (TH) inhalers in patients with asthma and/or COPD of varying severity. The primary endpoint was peak inspiratory flow (PIF) rate through the EH.ResultsThe intent-to-treat population comprised 397 patients; 383 patients were included in the per-protocol (PP) population. The mean PIF (standard deviation) values through the EH in patients <18 and ≥18 years of age with asthma and in those with COPD, were similar: 61.4 (11.5), 69.7 (13.5), and 61.9 (13.2) L/min, respectively. These flow rates correspond to pressure drops of 5.05 (1.80), 6.52 (2.34) and 5.19 (2.07) kPa, respectively. In total, 380 (99.2%) of patients in the PP population were able to generate a PIF rate through the EH of ≥30 L/min, which is required to enable consistent dose delivery from the DPI; there was a moderate direct association between age and PIF in younger patients with asthma, but this was inverse and less apparent in adult patients with asthma and/or those with COPD. Height and weight were also moderately correlated with PIF. Stronger associations with PIF were observed for some lung function parameters, particularly native PIF and forced inspiratory vital capacity.ConclusionsOver 99% of patients with asthma and/or COPD were able to inhale through the EH with an adequate PIF rate, irrespective of age, or severity of airway obstruction. This confirms that patients with asthma and/or COPD can achieve inspiratory flows via the EH DPI that are sufficient for its effective use.

Project description:BackgroundInhaler selection is important when managing respiratory conditions; a patient's inhalation technique should be appropriate for the selected device, and patients should ideally be able to use a device successfully regardless of disease severity. The NEXThaler is a multidose dry-powder inhaler with a breath-actuated mechanism (BAM) and dose counter that activates only following inhalation, so effectively an 'inhalation counter'. We assessed inspiratory flow through the NEXThaler in two studies and examined whether inhalation triggered the BAM.MethodsThe two studies were open-label, single-arm, and single visit. One study recruited patients with asthma aged ≥ 18 years; the other recruited patients with chronic obstructive pulmonary disease (COPD) aged ≥ 40 years. All patients inhaled twice through a placebo NEXThaler. The inspiratory profile through the device was assessed for each inhalation using acoustic monitoring, with flow at and time to BAM firing, peak inspiratory flow (PIF), and total inhalation time assessed.ResultsA total of 40 patients were enrolled in the asthma study: 20 with controlled asthma and 20 with partly controlled/uncontrolled asthma. All patients were able to trigger the BAM, as evidenced by the inhalation counter activating on closing the device. Mean flow at BAM firing following first inhalation was 35.0 (range 16.3-52.3) L/min; mean PIF was 64.6 (35.0-123.9) L/min. A total of 72 patients were enrolled in the COPD study, with data analysed for 69 (mean forced expiratory volume in 1 s 48.7% predicted [17-92%]). As with the asthma study, all patients, regardless of airflow limitation, were able to trigger the BAM. Mean flow at BAM firing following first inhalation was 41.9 (26.6-57.1) L/min; mean PIF was 68.0 (31.5-125.4) L/min. Device usability was rated highly in both studies, with 5 min sufficient to train the patients, and a click heard shortly after inhalation in all cases (providing feedback on BAM firing).ConclusionsInhalation flows triggering the BAM in the NEXThaler were similar between patients with controlled and partly controlled/uncontrolled asthma, and were similar across COPD airflow limitation. All enrolled patients were able to activate the device.

Project description:BackgroundIn patients receiving inhaled medication, dissatisfaction with and difficulty in using the inhaler can affect treatment adherence. The incidence of handling errors is typically higher in the elderly than in younger people. The aim of the study was to assess inhaler preference for and handling errors with the ELLIPTA® dry powder inhaler (DPI), (GSK), compared with the established BREEZHALER™, a single-dose capsule DPI (Novartis), in inhalation device-naïve Japanese volunteers aged ≥40 years.MethodsIn this open-label, nondrug interventional, crossover DPI preference study comparing the ELLIPTA DPI and BREEZHALER, 150 subjects were randomized to handle the ELLIPTA or BREEZHALER DPIs until the point of inhalation, without receiving verbal or demonstrative instruction (first attempt). Subjects then crossed over to the other inhaler. Preference was assessed using a self-completed questionnaire. Inhaler handling was assessed by a trained assessor using a checklist. Subjects did not inhale any medication in the study, so efficacy and safety were not measured.ResultsThe ELLIPTA DPI was preferred to the BREEZHALER by 89% of subjects (odds ratio [OR] 70.14, 95% confidence interval [CI] 33.69-146.01; P-value not applicable for this inhaler) for ease of use, by 63% of subjects (OR 2.98, CI 1.87-4.77; P<0.0001) for ease of determining the number of doses remaining in the inhaler, by 91% for number of steps required, and by 93% for time needed for handling the inhaler. The BREEZHALER was preferred to the ELLIPTA DPI for comfort of the mouthpiece by 64% of subjects (OR 3.16, CI 1.97-5.06; P<0.0001). The incidence of handling errors (first attempt) was 11% with ELLIPTA and 68% with BREEZHALER; differences in incidence were generally similar when analyzed by age (< or ≥65 years) or sex.ConclusionThese data, obtained in an inhalation device-naïve population, suggest that the ELLIPTA DPI is preferred to an established alternative based on its ease-of-use features and is associated with fewer handling errors.

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Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD.

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