Comparison of extrafine beclomethasone dipropionate/formoterol fumarate dry powder inhaler and pressurized metered-dose inhaler in Chinese patients with asthma: the FORTUNE study.

OBJECTIVE: When selecting inhaled therapies, it is important to consider both the active molecules and the device. Extrafine formulation beclomethasone dipropionate plus formoterol fumarate (BDP/FF) has been available for some years delivered via pressurized metered-dose inhaler (pMDI). More recently, a breath-activated, multi-dose dry-powder inhaler (DPI), the NEXThaler, has been approved. The current study aimed to demonstrate the non-inferiority of BDP/FF delivered via the DPI vs. via the pMDI, in Chinese adults with asthma. METHODS: After a four-week run-in period, when all patients received BDP/FF pMDI 100/6 µg, two inhalations twice daily (BID), patients were randomized equally to BDP/FF pMDI or DPI, both 100/6 µg, two inhalations BID for 12 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF DPI vs. BDP/FF pMDI in terms of average pre-dose morning peak expiratory flow (PEF) over the entire treatment period. RESULTS: Of 252 and 242 patients in the DPI and pMDI groups, respectively, 88.5% and 88.8% completed the study. The primary objective was met, with no statistically significant difference between the treatments in average pre-dose morning PEF, and with the lower limit of the 95% CI above the -15 L/min non-inferiority margin (adjusted mean difference: 5.25 L/min [95% CI: -0.56, 11.06]). Adverse events were reported by 48.4% and 49.6% patients in the DPI and pMDI groups, respectively, most mild or moderate. CONCLUSIONS: The NEXThaler DPI is a similarly effective device to the pMDI for the administration of BDP/FF in adults, so extending the options available for the management of asthma.

Pharmacokinetic profile of beclometasone dipropionate/formoterol fumarate administered through a novel dry-powder inhaler in Chinese healthy volunteers.

INTRODUCTION: An extrafine formulation of the inhaled corticosteroid beclometasone dipropionate (BDP) plus the long-acting ß2-agonist formoterol fumarate (FF) has been available for years via a pressurised metered-dose inhaler for the management of asthma and chronic obstructive pulmonary disease. More recently, the same extrafine BDP/FF formulation has become available in a multidose dry-powder inhaler (DPI) called the NEXThaler. The pharmacokinetics (PK) of BDP/FF via this DPI have previously been evaluated in a Caucasian population. The current study aimed to evaluate the PK profile of BDP/FF via DPI in healthy Chinese volunteers. The results were then compared to previous Caucasian data. METHODS: This open-label parallel group study randomised subjects to single-dose BDP/FF 200/12, 400/24, or 800/48 µg via DPI. Blood samples were taken up to 24 h post-dose for PK evaluation of BDP, beclometasone 17-monopropionate (B17MP, active metabolite of BDP) and formoterol. The primary objective of the study was to evaluate the PK of BDP/FF (BDP, B17MP and formoterol). The study is registered on the World Health Organization International Clinical Trials Registry Platform (ChiCTR1900021899). RESULTS: Of 36 subjects randomised, all completed the study. Following inhalation of all three doses, plasma concentration of formoterol and BDP increased rapidly, with peak mean values at the first post-dose timepoint (5 min), then rapidly decreasing; B17MP reached peak concentration slightly later. Plasma exposure to formoterol, BDP and B17MP increased broadly in a dose-proportional manner to BDP/FF dose, with tmax values similar across the dose range. All BDP/FF doses were generally well tolerated. CONCLUSIONS: Therapeutic and supra-therapeutic doses of BDP/FF administered via DPI resulted in approximately dose-proportional plasma exposure in healthy Chinese subjects, with PK profiles that were comparable to previous data from Caucasian subjects.

Real-world use of inhaled corticosteroid/formoterol as needed in adults with mild asthma: the PRIME study.

Introduction: Inhaled corticosteroid/formoterol fumarate (ICS/FF) as needed is recommended by the Global Initiative for Asthma (GINA) as sole therapy in adults with mild asthma, with low-dose maintenance ICS plus short-acting ß2-agonist (SABA) as an alternative. SABA alone is no longer recommended. Given these changes in recommendations, the observational PRIME study aimed to describe real-world treatment patterns in mild asthma in Europe. Methods: Adults with asthma receiving low-dose maintenance ICS, or as needed ICS/FF or SABA were followed for 6 months. Data collected included Asthma Control Test (ACT), Asthma Control Questionnaire 5-item (ACQ-5), forced expiratory volume in 1 s (FEV1) and asthma exacerbations. Results: The study was conducted in 883 patients in Germany, Italy, Poland and Spain; 833 (94.3%) completed follow-up. At enrolment, 32.2% received maintenance ICS, 56.3% ICS/FF as needed and 11.6% SABA as needed; 57.4%, 61.2% and 54.9%, respectively, had well-controlled asthma (ACQ-5/ACT definition). After 6 months, changes in mean FEV1 were small in the maintenance ICS and ICS/FF as needed groups, whereas there was a decline in FEV1 in the SABA as needed group. ACQ-5 total score improved from baseline in all three groups; 0.4%, 0.4% and 2.0% patients, respectively, had a severe exacerbation during the study. Conclusions: More patients received ICS/FF as needed than SABA as needed, suggesting that physicians are aware of the latest treatment recommendations. This real-world study provides additional support to the use of ICS/FF as needed as preferred treatment for patients with mild asthma, whereas SABA as needed was associated with a fall in lung function and more severe exacerbations.

Artificial intelligence based software facilitates spirometry quality control in asthma and COPD clinical trials.

Rationale: Acquiring high-quality spirometry data in clinical trials is important, particularly when using forced expiratory volume in 1 s or forced vital capacity as primary end-points. In addition to quantitative criteria, the American Thoracic Society (ATS)/European Respiratory Society (ERS) standards include subjective evaluation which introduces inter-rater variability and potential mistakes. We explored the value of artificial intelligence (AI)-based software (ArtiQ.QC) to assess spirometry quality and compared it to traditional over-reading control. Methods: A random sample of 2000 sessions (8258 curves) was selected from Chiesi COPD and asthma trials (n=1000 per disease). Acceptability using the 2005 ATS/ERS standards was determined by over-reader review and by ArtiQ.QC. Additionally, three respiratory physicians jointly reviewed a subset of curves (n=150). Results: The majority of curves (n=7267, 88%) were of good quality. The AI agreed with over-readers in 91% of cases, with 97% sensitivity and 93% positive predictive value. Performance was significantly better in the asthma group. In the revised subset, n=50 curves were repeated to assess intra-rater reliability (κ=0.83, 0.86 and 0.80 for each of the three reviewers). All reviewers agreed on 63% of 100 unique tests (κ=0.5). When reviewers set the consensus (gold standard), individual agreement with it was 88%, 94% and 70%. The agreement between AI and "gold-standard" was 73%; over-reader agreement was 46%. Conclusion: AI-based software can be used to measure spirometry data quality with comparable accuracy as experts. The assessment is a subjective exercise, with intra- and inter-rater variability even when the criteria are defined very precisely and objectively. By providing consistent results and immediate feedback to the sites, AI may benefit clinical trial conduct and variability reduction.

Comparison of the Asthma Control Questionnaire and patient diaries in uncontrolled asthma.

These post hoc analyses suggest that the Asthma Control Questionnaire and eDiary have different measurement properties, and it is therefore potentially valuable to include both in clinical trials https://bit.ly/3TIYClX.

Targeting the Small Airways with Inhaled Corticosteroid/Long-Acting Beta Agonist Dry Powder Inhalers: A Functional Respiratory Imaging Study.

Background: Peripheral deposition of inhaled medication is important as small airway disease has a key role in asthma. In this study, we compared the lung deposition at different mean flow rates of three inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combinations delivered by dry powder inhaler (DPI), that is, Foster NEXThaler® (extrafine formulation of beclomethasone/formoterol), Relvar Ellipta® (fluticasone furoate/vilanterol trifenatate), and Symbicort Turbohaler® (budesonide/formoterol). Materials and Methods:In vitro drug delivery parameters were applied to lung computerized tomography (CT) scans of 20 asthma patients by functional respiratory imaging (FRI). Aerosol airway deposition patterns were calculated as percentage (standard deviation) intrathoracic versus extrathoracic deposition, percentage peripheral deposition, and central-to-peripheral (C/P) ratio at different inspiratory mean flow rates. Results: At 60 and 40 L/min, intrathoracic deposition of ICS/LABA was significantly higher with NEXThaler versus Ellipta. Peripheral deposition (60 L/min) with NEXThaler was higher than Ellipta for ICS (24.7% [3.5%] vs. 5.0% [2.0%]; p < 0.001) and LABA (25.3% [3.5%] vs. 13.0% [3.0%]; p < 0.001). C/P ratio with NEXThaler was lower (indicating higher peripheral deposition) than Ellipta (ICS: 0.63 vs. 1.63; LABA: 0.63 vs. 0.99). Inspiratory flow rate did not impact lung deposition with NEXThaler or Ellipta. In contrast, Turbohaler performance was negatively impacted by decreasing inspiratory flow rate. In fact, although lung deposition with Turbohaler was similar to that of NEXThaler at 60 L/min, lung deposition with Turbohaler was significantly lower than NEXThaler at both 40 L/min (∼30%) and 30 L/min (∼50%). Conclusions: Using FRI, we demonstrated better peripheral deposition and C/P ratios of ICS/LABA with NEXThaler versus Ellipta. NEXThaler demonstrated inspiratory flow rate independency of lung deposition versus Turbohaler. These findings suggest that the extrafine formulation is superior to large particle formulations in delivering ICS/LABA consistently both to the large and small airways.

Airway Deposition of Extrafine Inhaled Triple Therapy in Patients with COPD: A Model Approach Based on Functional Respiratory Imaging Computer Simulations.

Introduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting ß2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs. Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients' high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition. Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were <1, indicating greater peripheral than central deposition (0.48±0.13, 0.48±0.13 and 0.49±0.13 for BDP, FF and GB, respectively; 1.96±0.84, 0.97±0.34 and 1.20±0.48 for FluF, VI and UMEC, respectively). Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB.