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      Is Open Access

      Dose–response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT)

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          Abstract

          Introduction

          An extrafine formulation of the long-acting muscarinic antagonist, glycopyrronium bromide (GB), has been developed for delivery via the NEXThaler dry powder inhaler (DPI). This study assessed the bronchodilator efficacy and safety of different doses of this formulation in patients with COPD to identify the optimal dose for further development.

          Patients and methods

          This was a multicenter, randomized, double-blind, placebo-controlled, incomplete block, three-way crossover study, including three 28-day treatment periods, each separated by a 21-day washout period. Eligible patients had a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 s (FEV 1) 40%–70% predicted. Treatments administered were GB 6.25, 12.5, 25 and 50 μg or matched placebo; all were given twice daily (BID) via DPI, with spirometry assessed on Days 1 and 28 of each treatment period. The primary end point was FEV 1 area under the curve from 0 to 12 h (AUC 0–12 h) on Day 28.

          Results

          A total of 202 patients were randomized (61% male, mean age 62.6 years), with 178 (88%) completing all the three treatment periods. For the primary end point, all the four GB doses were superior to placebo ( p<0.001) with mean differences (95% CI) of 114 (74, 154), 125 (85, 166), 143 (104, 183) and 187 (147, 228) mL for GB 6.25, 12.5, 25 and 50 μg BID, respectively. All four GB doses were also statistically superior to placebo for all secondary efficacy end points, showing clear dose–response relationships for most of the endpoints. Accordingly, GB 25 μg BID met the criteria for the minimally acceptable dose. Adverse events were reported by 15.5, 16.2, 10.9 and 14.3% of patients receiving GB 6.25, 12.5, 25 and 50 μg BID, respectively, and 14.8% receiving placebo.

          Conclusion

          This study supports the selection of GB 25 μg BID as the minimal effective dose for patients with COPD when delivered with this extrafine DPI formulation.

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          Most cited references 10

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          Bronchodilator responsiveness in patients with COPD.

          The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease (COPD) patients, and depends upon the type and dose of bronchodilator and the timing of administration. Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, a 4-yr randomised double-blind trial evaluating the efficacy of 18 mug tiotropium daily in reducing the rate of decline in lung function. After wash-out of respiratory medications, patients received 80 mug ipratropium followed by 400 mug salbutamol. Spirometry was performed before and 90 min following ipratropium administration. The criteria used for forced expiratory volume in one second (FEV(1)) responsiveness were: >or=12% increase over baseline and >or=200 mL; >or=15% increase over baseline; and >or=10% absolute increase in the percentage predicted value. Of the patients, 5,756 had data meeting the criteria for analysis (age 64.5 yrs; 75% male; baseline FEV(1) 1.10 L (39.3% predicted) and forced vital capacity (FVC) 2.63 L). Compared with baseline, mean improvements were 229 mL in FEV(1) and 407 mL in FVC. Of these patients, 53.9% had >or=12% and >or=200 mL improvement in FEV(1), 65.6% had >or=15% improvement in FEV(1), and 38.6% had >or=10% absolute increase in FEV(1) % pred. The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators.
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            Importance of inhaler devices in the management of airway disease.

            The delivery of drugs by inhalation is an integral component of asthma and chronic obstructive pulmonary disease (COPD) management. However, even with effective inhaled pharmacological therapies, asthma, particularly, remains poorly controlled around the world. The reasons for this are manifold, but limitations of treatment guidelines in terms of content, implementation and relevance to everyday clinical life, including insufficient patient education, access to health care and cost of medication as well as poor inhaler technique are likely to contribute. Considering that inhalation therapy is a cornerstone in asthma and COPD management, little advice is provided in the guidelines regarding inhaler selection. The pressurised metered dose inhaler (pMDI) is still the most frequently prescribed device worldwide, but even after repeated tuition many patients fail to use it correctly. In addition, the correct technique can be lost over time. Although several improvements in pMDIs such as a change in the propellant and actuation have resulted in improvements in lung deposition, many dry powder inhalers (DPIs) are easier to use. However, these devices also have limitations such as dependency of drug particle size on flow rate and loss of the metered dose if the patient exhales through the device before inhaling. Improvements in using inhalation devices more efficiently, in inhaler design for supporting patient compliance, and advances in inhaler technology to assure drug delivery to the lungs, have the potential to improve asthma and COPD management and control. New and advanced devices are considered being helpful to minimise the most important problems patients have with current DPIs.
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              Predictors of incorrect inhalation technique in patients with asthma or COPD: a study using a validated videotaped scoring method.

              Inadequate technique reduces the effects of inhalation medication. Errors in inhalation technique have been reported to range up to 85%. Not only various patients' characteristics but also the device has an effect on correct inhalation technique. The purpose of this study was to determine the effect of patients' characteristics and type of inhaler device on inhalation technique in patient with asthma or chronic obstructive pulmonary disease (COPD). A validated scoring method was used that consisted of triple viewing of video-recorded inhalations, using device-specific checklists. The following patient characteristics were investigated: gender, age, education level, diagnosis, treatment by a pulmonary physician, previously received inhalation instruction, exacerbation frequency, knowledge, self-management competence, pulmonary function, and use of multiple inhaler devices. Chi-square statistics were used for univariate associations between potential determinants and correctness of inhalation technique. Relevant determinants were entered into a multivariate logistic regression model. Moreover, inhalation technique errors were examined for six inhaler devices: three prefilled dry powder inhalers, one single-dose dry powder inhaler, a pressurized metered-dose inhaler (pMDI) and a pMDI with a spacer. Overall, 40% of the patients made at least one essential mistake in their inhalation technique. Patients who never received inhalation instruction and patients who used more than one inhaler device made significantly more errors (odds ratio both 2.2). Comparison between devices showed that a correct inhalation technique most likely occurred with the use of prefilled dry powder devices. Incorrect inhalation technique is common among asthma and COPD patients in a pulmonary outpatient clinic. Our study suggests that the use of prefilled dry powder inhalers as well as inhalation instruction increases correct inhalation technique. Simultaneous use of different types of inhalation devices has to be discouraged.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2018
                25 May 2018
                : 13
                : 1701-1711
                Affiliations
                [1 ]Insaf Respiratory Research Institute, Wiesbaden, Germany
                [2 ]Global Clinical Development, Chiesi S.A.S, Bois-Colombes, France
                [3 ]Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy
                Author notes
                Correspondence: Kai M Beeh, Insaf Respiratory Research Institute, Biebricher Allee 34, Wiesbaden, Germany, Tel +49 611 985 4347, Email k.beeh@ 123456insaf-wi.de
                Article
                copd-13-1701
                10.2147/COPD.S168493
                5973313
                © 2018 Beeh et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Clinical Trial Report

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