The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.

BACKGROUND: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough. METHODS: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed. RESULTS: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo. CONCLUSIONS: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168.

Interleukin-1 receptor antagonist anakinra as treatment for paradoxical responses in HIV-negative tuberculosis patients: A case series.

BACKGROUND: Paradoxical inflammatory responses can occur during microbiologically successful antituberculous therapy. Optimal treatment is unknown, but corticosteroids are used most often. It is likely that interleukin-1 (IL-1) plays a central role in the development of these paradoxical responses, and if corticosteroids fail or are undesirable because of adverse effects, anti-IL-1 therapy may therefore be a rational choice. METHODS: We present seven HIV-negative tuberculosis patients with paradoxical responses, two with exclusively pulmonary and five with extrapulmonary tuberculosis. All had received corticosteroids, with unsatisfactory effect. Patients were treated with the IL-1 receptor antagonist anakinra and monitored for reduction of fever and inflammatory markers, imaging evidence of stabilization or regression of lesions, and respiratory improvement. FINDINGS: Six patients had anemia and four patients had lymphopenia at the start of the antituberculosis treatment. Fever was present in six patients at the moment of paradoxical response. Anakinra resulted in the decrease of fever within days, followed by resolution of symptoms and radiological improvement in five patients. Anakinra induced neutropenia, necessitating its cessation in two patients, who recovered quickly afterward. CONCLUSION: Anakinra can be considered in HIV-negative tuberculosis patients with paradoxical responses when steroids fail or are undesired. Given its favorable safety profile and reversible side effects, it is conceivable that anakinra might also be used as first-line adjuvant treatment for paradoxical responses. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781).

Identifying a nasal gene expression signature associated with hyperinflation and treatment response in severe COPD.

Hyperinflation contributes to dyspnea intensity in COPD. Little is known about the molecular mechanisms underlying hyperinflation and how inhaled corticosteroids (ICS) affect this important aspect of COPD pathophysiology. To investigate the effect of ICS/long-acting ß2-agonist (LABA) treatment on both lung function measures of hyperinflation, and the nasal epithelial gene-expression profile in severe COPD. 117 patients were screened and 60 COPD patients entered a 1-month run-in period on low-dose ICS/LABA budesonide/formoterol (BUD/F) 200/6 one inhalation b.i.d. Patients were then randomly assigned to 3-month treatment with either a high dose BDP/F 100/6 two inhalations b.i.d. (n = 31) or BUD/F 200/6 two inhalations b.i.d. (n = 29). Lung function measurements and nasal epithelial gene-expression were assessed before and after 3-month treatment and validated in independent datasets. After 3-month ICS/LABA treatment, residual volume (RV)/total lung capacity (TLC)% predicted was reduced compared to baseline (p < 0.05). We identified a nasal gene-expression signature at screening that associated with higher RV/TLC% predicted values. This signature, decreased by ICS/LABA treatment was enriched for genes associated with increased p53 mediated apoptosis was replicated in bronchial biopsies of COPD patients. Finally, this signature was increased in COPD patients compared to controls in nasal, bronchial and small airways brushings. Short-term ICS/LABA treatment improves RV/TLC% predicted in severe COPD. Furthermore, it decreases the expression of genes involved in the signal transduction by the p53 class mediator, which is a replicable COPD gene expression signature in the upper and lower airways.Trial registration: ClinicalTrials.gov registration number NCT01351792 (registration date May 11, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 20, 2009), ClinicalTrials.gov registration number NCT00158847 (registration date September 12, 2005).

Effect of once-daily fluticasone furoate/vilanterol versus vilanterol alone on bone mineral density in patients with COPD: a randomized, controlled trial.

BACKGROUND: The relationship between inhaled corticosteroids and bone mineral density (BMD) remains uncertain despite extensive research. METHODS: This was an international, multicenter, randomized, double-blind, parallel-group, 3-year noninferiority study. Patients with chronic obstructive pulmonary disease (COPD) (⩾40 years of age; smoking history ⩾10 pack years) and at least one native hip evaluable for BMD were enrolled and randomized 1:1, stratified by sex, to treatment with vilanterol (VI) 25 µg or fluticasone furoate/vilanterol (FF/VI) 100 µg/25 µg. BMD measurements were taken via dual-energy X-ray absorptiometry every 6 months. The primary endpoint was assessment of the noninferiority of change from baseline in total hip BMD per year at the -1% noninferiority level. Change from baseline in BMD at the lumbar spine and BMD measurements by sex were secondary endpoints. Incidences of COPD exacerbations and bone fractures throughout the study were also recorded. RESULTS: Of 283 randomized patients, 170 (60%) completed the study. Noninferiority was demonstrated for FF/VI versus VI with regards to change from baseline in total hip BMD per year, with changes of -0.27% and 0.18%, respectively, and a treatment difference of -0.46% per year [95% confidence interval (CI) -0.97 to 0.06]. The treatment difference for FF/VI versus VI regarding lumbar spine BMD was -0.51% per year (95% CI -1.11 to 0.10). COPD exacerbations and bone fracture rates were similar between treatment groups. CONCLUSION: FF/VI showed noninferiority to VI for change from baseline in total hip BMD per year, when assessed at the -1% noninferiority margin in a combined sample of men and women with COPD.The reviews of this paper are available via the supplemental material section.

Critical Error Frequency and the Impact of Training with Inhalers Commonly used for Maintenance Treatment in Chronic Obstructive Pulmonary Disease.

Introduction: Training in correct inhaler use, ideally in person or by video demonstration, can minimize errors but is rarely provided in clinics. This open-label, low-intervention study evaluated critical error rates with dry-powder inhalers (DPIs), before and after training, in patients with chronic obstructive pulmonary disease. Methods: Patients prescribed an inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) (ELLIPTA, Turbuhaler, or DISKUS), long-acting muscarinic antagonist (LAMA)/LABA (ELLIPTA or Breezhaler), or LAMA-only DPI (ELLIPTA, HandiHaler, or Breezhaler) were enrolled. Critical errors were assessed before training (Visit 1 [V1]; primary endpoint) and 6 weeks thereafter (Visit 2 [V2]; secondary endpoint). Logistic regression models were used to calculate odds ratios (ORs) for between-group comparisons. Results: The intent-to-treat population comprised 450 patients. At V1, fewer patients made ≥1 critical error with ELLIPTA (10%) versus other ICS/LABA DPIs (Turbuhaler: 40%, OR 4.66, P=0.005; DISKUS: 26%, OR 2.48, P=0.114) and other LAMA or LAMA/LABA DPIs (HandiHaler: 34%, OR 3.50, P=0.026; Breezhaler: 33%, OR 3.94, P=0.012). Critical error rates with the primary ICS/LABA DPI were not significantly different between ELLIPTA ICS/LABA (10%) and ICS/LABA plus LAMA groups (12-25%). Critical errors with the primary ICS/LABA DPI occurred less frequently with ELLIPTA ICS/LABA with or without LAMA (11%) versus Turbuhaler ICS/LABA with or without LAMA (39%, OR 3.99, P<0.001) and DISKUS ICS/LABA with or without LAMA (26%, OR 2.18, P=0.069). Simulating single-inhaler versus multiple-inhaler triple therapy, critical error rates were lower with ELLIPTA fluticasone furoate/vilanterol (FF/VI; 10%) versus ELLIPTA FF/VI plus LAMA (22%), considering errors with either DPI (OR 2.50, P=0.108). At V2, critical error rates decreased for all DPIs/groups, reaching zero only for ELLIPTA. Between-group comparisons were similar to V1. Conclusion: Fewer patients made critical errors with ELLIPTA versus other ICS/LABA, and LAMA or LAMA/LABA DPIs. The effect of "verbal" training highlights its importance for reducing critical errors with common DPIs.

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Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression.

BACKGROUND: Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium. METHODS: Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls. RESULTS: In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate < 0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDRGSEA < 0.001). CONCLUSION: We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008).

Population Pharmacokinetics and Pharmacodynamics of GSK961081 (Batefenterol), a Muscarinic Antagonist and ß2-Agonist, in Moderate-to-Severe COPD Patients: Substudy of a Randomized Trial.

GSK961081 (batefenterol) is a novel bifunctional molecule composed of a muscarinic antagonist and a ß2-agonist. The aims of this substudy were (1) to characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of GSK961081 in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD); and (2) to investigate the relationship between systemic exposure to GSK961081 and key cardiac-related safety parameters. Three once-daily doses (100, 400, and 800 µg) and three twice-daily doses (100, 200, and 400 µg) of GSK961081 DISKUS were investigated. A two-compartment disposition PK model with first-order absorption adequately described the plasma GSK961081 concentration-time data. An empirical maximum-effects PD model adequately described the forced expiratory volume in 1 s (FEV1) response relationship with the covariate baseline FEV1 on day 1. No clear relationships between GSK961081 plasma drug levels and cardiac-related safety parameters were apparent. The PK and PD models will be used to guide the dose selection and development of GSK961081 in patients with COPD.

A new class of bronchodilator improves lung function in COPD: a trial with GSK961081.

GSK961081 is a bifunctional molecule demonstrating both muscarinic antagonist and ß-agonist activities. This was a 4-week, multicentre, randomised, double-blind, double-dummy, placebo and salmeterol controlled parallel group study. Doses ranging across three twice-daily doses and three once-daily doses were assessed in moderate and severe chronic obstructive pulmonary disease (COPD) patients. Trough forced expiratory volume in 1 s (FEV1) at day 29 was the primary end-point. At days 1 and 28, 12-h FEV1 spirometry was performed in all patients. A subset of patients underwent complete 24-h spirometry at day 28. The study recruited 436 patients. GSK961081 showed statistically and clinically significant differences from placebo in all doses and regimens for trough FEV1 on day 29 (155-277 mL). The optimal total daily dose was 400 µg, either as 400 µg once daily or as 200 µg twice daily, with an improvement in day 29 trough FEV1 of 215 mL and 249 mL, respectively. Other efficacy end-points also showed improvement. No effects were observed on glucose, potassium, heart rate, blood pressure and no dose-response effect was seen on corrected QT elongation. This study showed that GSK961081 is an effective bronchodilator in COPD and appeared to be safe and well tolerated.

Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial.

BACKGROUND: There is a pressing need for new forms of treatment for COPD. Based on the known pathophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to-severe COPD. METHODS: This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-6-week period to eliminate any remaining effects of previous medication, 55 patients received oral AZD1236 75 mg or matching placebo twice daily for 6 weeks. Differential cell count and TNF-α levels in induced sputum and 24-h urinary desmosine excretion were the main study variables, but a range of exploratory biomarkers was also assessed in induced sputum, blood and urine. Secondary variables included lung function and patient-recorded Clinical COPD Questionnaire (CCQ) responses and diary records of symptoms, adverse events, use of rescue medication and AZD1236 plasma concentrations. RESULTS: The majority of variables showed little change compared to placebo although there was a possible, but not statistically significant reduction in urinary desmosine excretion and reductions in the number and percentage of lymphocytes in sputum and blood with AZD1236. No effect was seen on clinical parameters after 6 weeks of treatment. The proportion of patients experiencing adverse events was similar in both treatment groups. CONCLUSIONS: AZD1236 dosed orally at 75 mg twice daily was generally well tolerated over 6 weeks in patients with moderate-to-severe COPD. No clinical efficacy of AZD1236 was demonstrated in this short-term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials.

Efficacy of formoterol Turbuhaler in the emergency treatment of patients with obstructive airway diseases.

Dry powder devices are rarely used in the emergency room (ER) treatment of acute and severe bronchoconstriction due to hesitations with respect to clinical efficacy. This study investigated the effects of two inhalers with formoterol in patients visiting the ER Department for acute and severe dyspnoea, mainly exacerbations of chronic obstructive pulmonary disease. Two doses of 12mug formoterol were given at enrolment, either via Turbuhaler or via pressurised metered dose inhaler, connected to a spacer device (pMDI+S) in a double-blind way and parallel design. Another two doses of 12 microg formoterol were given after 30 min. Forced expiratory volume in the 1s (FEV(1)) and Borg dyspnoea score were assessed until 60 min. The study was designed to test non-inferiority in effects on FEV(1). Seventy-seven patients were enrolled with a mean age of 66 years and a FEV(1) of 1.03 L (39% of predicted). The effects of the two treatments were almost identical. The mean improvement in FEV(1) at 60 min after formoterol Turbuhaler was 94% of the improvement after formoterol pMDI+S. A statistically significant non-inferiority was shown (p=0.037) at 60 min (primary endpoint) as well as at 5 and 30 min (secondary endpoints, p=0.0043 and 0.013, respectively). Improvements in the Borg dyspnoea score and other lung-function parameters did not differ significantly between the two devices. In conclusion, formoterol Turbuhaler was equally effective as formoterol pMDI+S in the treatment of acute bronchoconstriction within the ER.

Increased systemic inflammation is a risk factor for COPD exacerbations.

BACKGROUND: COPD is characterized by episodic increases in respiratory symptoms, so-called exacerbations. COPD exacerbations are associated with an increase in local and systemic inflammation. Data of a previously published study in a well-characterized COPD cohort were analyzed to define predictive factors of acute exacerbations, particularly focusing on systemic inflammation. OBJECTIVE: To determine if an elevated systemic inflammatory status measured at baseline is related to the occurrence of acute exacerbations in patients with COPD. METHODS: The occurrence of moderate (requiring oral prednisolone) and severe exacerbations (requiring hospitalization) was prospectively recorded over 1 year. At the beginning of the study, lung function values (FEV1, FVC, functional residual capacity, and diffusion capacity of the lung for carbon monoxide [Dlco]) and serum levels of C-reactive protein, fibrinogen, lipopolysaccharide binding protein, tumor necrosis factor (TNF)-alpha, and its soluble receptors (soluble TNF receptors 55 and 75) as markers of systemic inflammation were determined. RESULTS: Two hundred seventy-seven person-years of follow-up were analyzed in the total group of 314 patients: 186 patients were responsible for 411 exacerbations (374 moderate and 37 severe). Multivariate analyses showed that a higher initial fibrinogen level and a lower FEV1 predicted a higher rate of both moderate and severe exacerbations. Additional independent predictors of a severe exacerbation were a higher number of prestudy severe exacerbations and lower Dlco. A higher number of prestudy moderate exacerbations was the only additional independent risk factor for the rate of moderate exacerbations. CONCLUSION: This study demonstrates that besides lung function impairment systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients to reduce the burden of exacerbations.

Surgical mediastinal staging in daily practice.

STUDY OBJECTIVES: An adequately staged mediastinum remains obligatory in patients with NSCLC prior to surgery. In this study, we investigated the accuracy of preoperative surgical mediastinal staging procedures in four hospitals. SETTING: Non-university teaching hospital and three surrounding community hospitals in Eindhoven, The Netherlands. PATIENTS, MEASUREMENTS AND RESULTS: Patients with NSCLC who underwent mediastinoscopy and/or thoracotomy, between 1993 and 1999. Adherence to guidelines for indicating and performing mediastinoscopy were investigated and compared in four hospitals. Guidelines for indicating mediastinoscopy were adequately followed in two-thirds of cases. Mediastinoscopy was performed according to gold standards in 40% of cases. The hospital with the smallest number of evaluated patients scored the worst. Postoperatively, 17% of patients appeared to have "unforeseen N2-3 disease". In approximately 18% of these "upstaged" patients, thoracotomy could have been prevented, if guidelines had been followed adequately. CONCLUSIONS: In clinical practice the adherence to staging guidelines with respect to mediastinoscopy is insufficient in one-third of patients. Furthermore, mediastinoscopy was performed according to gold standards in 40% of patients.