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      Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD

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          Abstract

          Background

          CHF6001 is a novel inhaled phosphodiesterase-4 inhibitor. This Phase IIa study assessed the effects of CHF6001 on markers of inflammation in induced sputum and blood in patients with chronic obstructive pulmonary disease (COPD).

          Methods

          This was a multicentre, three-period (each 32 days), three-way, placebo-controlled, double-blind, complete-block crossover study. Eligible patients had COPD, chronic bronchitis, and were receiving inhaled triple therapy for ≥2 months. Patients received CHF6001 800 or 1600 μg, or matching placebo twice daily via multi-dose dry-powder inhaler (NEXThaler). Induced sputum was collected pre-dose on Day 1, and post-dose on Days 20, 26 and 32. Blood was sampled pre-dose on Day 1, and pre- and post-dose on Day 32.

          Results

          Of 61 randomised patients, 54 (88.5%) completed the study. There were no significant differences between groups for overall sputum cell count, or absolute numbers of neutrophils, eosinophils or lymphocytes. CHF6001 800 μg significantly decreased the absolute number and percentage of macrophages vs placebo.

          In sputum, compared with placebo both CHF6001 doses significantly decreased leukotriene B4, C-X-C motif chemokine ligand 8, macrophage inflammatory protein 1β, matrix metalloproteinase 9, and tumour necrosis factor α (TNFα). In blood, both CHF6001 doses significantly decreased serum surfactant protein D vs placebo. CHF6001 1600 μg significantly decreased TNFα ex-vivo (after incubation with lipopolysaccharide).

          Conclusion

          The data from this study show that CHF6001 inhaled twice daily has anti-inflammatory effects in the lungs of patients with COPD already treated with triple inhaled therapy.

          Trial registration

          The study is registered on ClinicalTrials.gov ( NCT03004417).

          Electronic supplementary material

          The online version of this article (10.1186/s12931-019-1142-7) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references 25

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          The nature of small-airway obstruction in chronic obstructive pulmonary disease.

          Chronic obstructive pulmonary disease (COPD) is a major public health problem associated with long-term exposure to toxic gases and particles. We examined the evolution of the pathological effects of airway obstruction in patients with COPD. The small airways were assessed in surgically resected lung tissue from 159 patients--39 with stage 0 (at risk), 39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The progression of COPD was strongly associated with an increase in the volume of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates containing follicles (P=0.003) and the absolute volume of B cells (P=0.03) and CD8 cells (P=0.02) also increased as COPD progressed. Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles. These changes are coupled to a repair or remodeling process that thickens the walls of these airways. Copyright 2004 Massachusetts Medical Society
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            The cytokine network in asthma and chronic obstructive pulmonary disease.

             Peter Barnes (2008)
            Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases.
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              • Article: not found

              Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.

              The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD. In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 microg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125. Patients were assigned to treatment, stratified according to smoking status and treatment with longacting beta(2) agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV(1) increased by 48 mL with roflumilast compared with placebo (p<0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [95% CI 8-25], p<0.0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was -2.17 kg. Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies. Nycomed.
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                Author and article information

                Contributors
                +39 0521 279 780 , M.Govoni@chiesi.com
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                9 August 2019
                9 August 2019
                2019
                : 20
                Affiliations
                [1 ]ISNI 0000000121662407, GRID grid.5379.8, Medicines Evaluation Unit, , The University of Manchester, Manchester University NHS Foundation Trust, ; Manchester, UK
                [2 ]GRID grid.488290.f, Insaf Respiratory Research Institute, ; Wiesbaden, Germany
                [3 ]GRID grid.476974.f, Celerion, ; Belfast, UK
                [4 ]IKF Pneumologie Frankfurt, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany
                [5 ]The Heart Lung Centre, London, UK
                [6 ]Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research, Grosshansdorf, Germany
                [7 ]ISNI 0000 0004 1761 6733, GRID grid.467287.8, Global Clinical Development, , Chiesi, ; Parma, Italy
                Article
                1142
                10.1186/s12931-019-1142-7
                6688371
                31399091
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100007560, Chiesi Farmaceutici;
                Award ID: Not applicable
                Award Recipient :
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                Research
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                © The Author(s) 2019

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