Comparison of the effect of beclometasone/formoterol in asthma patients after methacholine-induced bronchoconstriction: A noninferiority study using metered dose vs. dry powder inhaler.

AIMS: To demonstrate the noninferiority of extrafine beclomethasone/formoterol fumarate (BDP/FF) dry powder inhaler (DPI) vs. extrafine BDP/FF pressurized metered dose inhaler (pMDI; Foster® 100/6 µg NEXThaler and pMDI, respectively) in the onset of reliever effect after methacholine induced bronchospasm in asthmatic patients, evaluated in terms of forced expiratory volume in 1 s (FEV1 ) at 5 min postdose. The DPI provides an alternative device option for patients who cannot use a pMDI properly during an acute asthma attack. METHODS: Sixty-five patients received one inhalation of BDP/FF DPI, BDP/FF pMDI or placebo after methacholine challenge, according to a double-blind, double-dummy, cross-over design. Lung function and Borg dyspnoea score were assessed up to 30 min postdose. RESULTS: FEV1 adjusted mean difference between BDP/FF DPI and BDP/FF pMDI at 5 min postdose was 2 ml (95% confidence interval: -0.060; 0.065). A similar result was observed at the other time points. Median time to 85% recovery in FEV1 was 8 min for BDP/FF DPI, 7.5 min for BDP/FF pMDI and 28 min for placebo (P = 0.554 DPI vs. pMDI). The Borg score improved after treatment with both BDP/FF DPI and pMDI and the effect was greater than after placebo. Median time to reach 50% recovery was 4.2 min for BDP/FF DPI, 4.0 min for BDP/FF pMDI and 10.0 min for placebo (P = 0.609 DPI vs. pMDI). CONCLUSIONS: Extrafine Foster® NEXThaler, a flow-independent DPI, is comparable to extrafine Foster® pMDI when administered as reliever therapy after methacholine challenge, thus supporting the maintenance and reliever therapy approach also with Foster® NEXThaler.

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.

Discovery of a novel HCV helicase inhibitor by a de novo drug design approach.

Herein we report a successful application of a computer-aided design approach to identify a novel HCV helicase inhibitor. A de novo drug design methodology was used to generate an initial set of structures that could potentially bind to a putative binding site. Further structure refinement was carried out through docking a series of focused virtual libraries. The most promising compound was synthesised and it exhibited a submicromolar inhibition of the HCV helicase.