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Abstract Background The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication. Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD. Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients. Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers. The effects of disease severity, age and gender on PIF rate were also evaluated. Methods This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece. For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis. A paired t-test was performed to compare mean PIFs between each combination of devices. Results In total, 97 COPD patients were enrolled and completed the study. The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population. A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders. Conclusions Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers. These results were similar irrespective of patients’ COPD severity, age or gender. Trial registration The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.

Marc Miravitlles,1 Jéssica Montero-Caballero,2 Frank Richard,2 Salud Santos,3 Juan Luis Garcia-Rivero,4 Francisco Ortega,5 Xavier Ribera61Pneumology Department, Hospital Universitari Vall d’Hebron, Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 2Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 3Pulmonology Department, Hospital Universitari de Bellvitge, IDIBELL, Universitat de Barcelona, Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 4Pneumology Department, Hospital de Laredo, Cantabria, Spain; 5Pneumology Department, Hospital Virgen del Rocío, Sevilla, Spain; 6Boehringer Ingelheim Pharma GmbH & Co KG, Barcelona, Spain Abstract: Delivery of inhaled medications via an inhaler device underpins the effectiveness of treatment for patients with chronic obstructive pulmonary disease (COPD). Correct inhaler technique among patients is also a predictor of achieving treatment compliance and adherence. Reporting of patient satisfaction with inhalers is therefore gaining increasing attention and is now recognized as an important patient-reported outcome in clinical trials involving patients with COPD or asthma. In this cross-sectional study, we use the validated Patient Satisfaction and Preference Questionnaire (PASAPQ) to assess the handling and satisfaction for Respimat® Soft Mist™ Inhaler (SMI) compared with the Breezhaler® dry powder inhaler (DPI) among patients with COPD in Spain. Patients were already assigned to therapy with either SPIRIVA® (tiotropium) Respimat® or with Hirobriz®/Onbrez®/Oslif® (indacaterol) Breezhaler® for at least 3 but not more than 6 months before completing the PASAPQ at a single visit to the study site. The primary endpoint of the trial was the mean total PASAPQ score. Secondary endpoints were the performance score domain of the PASAPQ, the convenience score domain of the PASAPQ, and the overall satisfaction score of the PASAPQ. For the primary endpoint, the mean PASAPQ total score in the Respimat® and Breezhaler® groups was 80.7 and 79.9, respectively (difference of 0.8, 95% confidence interval [CI] −2.9 to 4.5; P=0.67). The mean total performance scores were 82.5 and 78.2 (difference of 4.3, 95% CI −0.3 to 8.9; P=0.06), and the mean total convenience scores were 78.6 and 81.9 (difference of −3.3, 95% CI −7.0 to 0.4; P=0.08) for the Respimat® and Breezhaler® groups, respectively. Patients gave the Respimat® SMI and the Breezhaler® DPI overall satisfaction PASAPQ scores of 6.0 and 5.9, respectively, which shows that patients were satisfied with these inhalers.Keywords: COPD, Respimat®, Breezhaler®, inhaler, handling

The effect of breathing parameters on the airway deposition of the inhaled aerosols with known size was intensively studied in the literature. However, in the case of dry powder aerosol drugs both the quantity and quality of the particles emitted by the inhaler and inhaled by the patients is a complex function of the patient's breathing parameters, which in turn depend also on the disease severity and current status of the patient. The aim of this study was to evaluate the impact of breathing parameters, gender, age, symptoms and exacerbation history related disease severity (GOLD groups) of chronic obstructive pulmonary disease (COPD) patients on the lung dose of four different drugs emitted by three DPIs (dry powder inhalers). Breathing profiles of 47 COPD patients were recorded while they inhaled through Turbuhaler®, Breezhaler® and Genuair® inhalers. Patient specific emitted doses and particle size distributions were determined for Symbicort® Turbuhaler®, Onbrez® Breezhaler®, Seebri® Breezhaler® and Bretaris® Genuair® aerosol drugs. Airway deposition was quantified by a validated whole respiratory tract particle deposition model. Correlation analysis of the lung doses with breathing parameters through the devices and with standard spirometric parameters was performed. The effects of gender, age and degree of disease severity (GOLD groups) on the lung doses were also studied by statistical analysis. Mean values and distributions of the deposited lung doses proved to be both drug and device specific, yielding 24.2 (±7.8), 22.6 (±3.6), 34.2 (±4.8) and 23.9 (±5.4) % values for Symbicort®, Onbrez®, Seebri® and Bretaris®, respectively. Drugs with flow rate sensitive emitted dose and emitted particle size distribution exhibited higher intersubject variability of the lung doses. The degree of correlation of lung doses with breathing parameters through the devices was also drug specific. Correlation with flow rate was the strongest for Symbicort® Turbuhaler®. Longer breath-hold increased the lung dose of all the studied drugs. Correlations of lung dose with standard spirometric parameters was generally weaker than its correlation with the parameters measured when inhaling through the devices. Men had higher lung deposition than women, younger patients had higher deposition than older ones and patients with less severe disease higher doses than those with more severe COPD, but the differences were statistically significant only upon gender and only in case of Symbicort® and Seebri®. Patients with better inhalation parameters are likely to have higher lung deposition when inhaling a drug with emitted dose and particle size distribution sensitive to the inhalation flow rate. At the same time, patients with lower lung capacity show better deposition results when inhaling from inhalers emitting a more constant amount of drug and particles with more stable aerodynamic characteristics. A more powerful inhalation significantly increases the lung dose for the drug emitted by Turbuhaler®, while long breath-hold is likely to yield significantly higher deposition for drugs emitted by Breezhaler® and Genuair®. Lung doses of two different drugs dispensed in the same inhaler can be significantly different. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Indacaterol (IND), is co-formulated with glycopyrronium (GLY), and mometasone furoate (MF) as a once-daily (o.d.) inhaled fixed-dose combination (IND/GLY/MF) delivered via the Breezhaler® device for maintenance treatment of asthma. We evaluated the steady state plasma pharmacokinetics (PK) of IND, GLY and MF following inhalation of IND/GLY/MF or as monotherapies. This was a randomized, open-label, four-way crossover study. Subjects received IND/GLY/MF 150/50/160 μg (high-dose), IND 150 μg, GLY 50 μg or MF 190 μg (in vitro fine particle mass comparable to 160 μg MF in IND/GLY/MF) via the Breezhaler® device, o.d. for 14 days in each period, with a washout of at least 7 days. PK was characterized on Day 14, up to 24 h post-dose. In total, 36 healthy subjects were randomized. For IND, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.922 (0.878, 0.969) and 1.02 (0.967, 1.08), respectively for the IND/GLY/MF versus IND monotherapy comparison. For GLY, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.986 (0.944, 1.03) and 1.21 (1.09, 1.34), respectively for the IND/GLY/MF versus GLY comparison. For MF, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 1.16 (1.09, 1.24) and 1.17 (1.09, 1.25), respectively for IND/GLY/MF versus MF comparison. Similar systemic exposure was noted for IND/GLY/MF versus monotherapy for all three mono-components, indicating a lack of PK interaction. Multiple inhaled doses of IND, GLY and MF were safe and well tolerated, when administered alone or in combination. There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF. • Inhalation of Indacaterol (IND), glycopyrronium (GLY), and mometasone furoate (MF), administered alone or as IND/GLY/MF combination via the Breezhaler® device over 14 days was safe and well tolerated. • There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF. [ABSTRACT FROM AUTHOR]

Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting β 2 -agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 μg) and high (320 μg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 μg) and high (800 μg) doses respectively, delivered via Twisthaler®. This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 μg) and high (320 μg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 μg) and high (800 μg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV 1), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 μg and 320 μg delivered via Breezhaler®, and MF 200 μg and 800 μg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment. The LS mean difference in trough FEV 1 after four weeks of treatment between MF low dose 80 μg (Breezhaler®) and MF low dose 200 μg (Twisthaler®) was 27 mL (95% CI –34, 89); for MF high dose 320 μg (Breezhaler®) and MF high dose 800 μg (Twisthaler®) the difference was 0 mL (95% CI –60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events. The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 μg) and high (320 μg) doses delivered with Breezhaler® with MF at low (200 μg) and high (800 μg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses. [ABSTRACT FROM AUTHOR]

Background: Addition 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 Methods: In 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., Results: A 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., Conclusion: In 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.