Triple Therapy with Mometasone/Indacaterol/Glycopyrronium or Doubling the ICS/LABA Dose in GINA Step 4: IRIDIUM Analyses.

INTRODUCTION: GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4. METHODS: This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF)25-75%)], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52. RESULTS: A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV1 versus high-dose MF/IND (Δ 41 mL; 95% CI - 7-90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39-137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21-30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified. CONCLUSION: Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02571777.

Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV1, E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV1; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Living with sarcoidosis: Virtual roundtable dialogue with patients and healthcare professionals.

BACKGROUND: Sarcoidosis is a multisystem disease, characterised by the infiltration of various organs by non-necrotising granulomas. The disease's heterogeneity complicates the study of patients' experiences. OBJECTIVE: To gather insight into life experiences, unmet needs and views on hypothetically emerging treatment options among patients living with sarcoidosis. METHODS: Multinational, virtual, interactive, moderated discussion of specific questions between people with sarcoidosis, with experienced clinicians participating. RESULTS: Nine patients with sarcoidosis from Australia, Denmark, Germany, Italy, Japan and the US, and three clinicians took part. All patients had pulmonary sarcoidosis, self-assessed as mild by five patients. The path to diagnosis was convoluted, with up to four physicians and a large number of tests involved. There was agreement that the process would be improved by earlier referral to specialists. The patients made a clear distinction between 'living with a condition' (adapting to the disease) and 'being ill'. The concept of remission was viewed sceptically as disease might develop in multiple organs. Panellists had a pragmatic attitude to therapies: side effects during a treatment course were accepted if overall symptoms improved. When considering hypothetical new therapies, improved quality of life (QoL) was the most important need; improved tolerability had lower priority. New therapies should be targeted on reducing disease progression and improving symptoms and QoL rather than corticosteroid withdrawal. CONCLUSIONS: The interactive exchange provided insights into the need for earlier specialist referrals, distrust of the concept of remission in sarcoidosis, and the need for therapies targeted on reducing disease progression and improving symptoms and QoL.

Efficacy of once-daily, single-inhaler, fixed-dose combination of mometasone/indacaterol/glycopyrronium in patients with asthma with or without persistent airflow limitation: Post hoc analysis from the IRIDIUM study.

BACKGROUND: A novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ2-agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL. METHODS: Patients with post-bronchodilator FEV1 ≤80% of predicted and FEV1/FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV1, PEF, and FEF25%-75%) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 µg), high-dose MF/IND (320/150 µg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 µg). RESULTS: Of the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV1, FEF25%-75%, PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively. CONCLUSIONS: Once-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation.

A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler® or Twisthaler® in patients with asthma.

INTRODUCTION: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting ß2-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®. METHODS: 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 (FEV1), 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. RESULTS: The LS mean difference in trough FEV1 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. CONCLUSION: 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.

[The concept of bacterial species]. / Conceptul de specie bacteriana.

Prokaryotes are the most abundant living organisms and also most diverse from genetically and metabolically point of view, being responsible for the majority of biogeochemical processes playing the most important role in life cycle on the planet. Considering this, there is a general agreement among taxonomists, that there is a very small number of bacterial species recognized and described today, mostly because of controversial issues concerning bacterial species concept. One of the most accepted approaches, even today, is the polyphasic taxonomy because it is based on diverse information, obtained from classic taxonomy but also from molecular level. The development of new molecular techniques, especially sequencing rRNA genes conducted to an improved concept, that we intended to evaluate in this review, and even more, to reconstruction of group specific phylogenetic tree.