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This is a single-arm, open label, Phase II study of Roflumilast in stable-state non-cystic fibrosis bronchiectasis subjects.
Bronchiectasis refers to a suppurative lung condition characterized by pathological dilatation of bronchi. The predominant aetiology of bronchiectasis in the Western population is related to cystic fibrosis (CF), which is genetically determined. Bronchiectasis due to other causes are generally grouped under the term "non-CF bronchiectasis", which accounts for practically all cases that are seen commonly in Hong Kong and many other Chinese populations.
The main pathogenesis of non-CF bronchiectasis involves airway inflammation, abnormal mucus clearance and bacterial colonization, resulting in progressive airway destruction and distortion. The current treatment strategies mainly focus on targeting the key elements in the pathogenesis of non-CF bronchiectasis.
In patients with bronchiectasis, there is also neutrophilic inflammation as in COPD. It is hypothesized that roflumilast can improve airway inflammation, sputum volume and sputum inflammatory markers in patients with bronchiectasis.
This study aims to investigate the effect of short-term (4-week) treatment with roflumilast on neutrophilic airway inflammation in stable-state non-CF bronchiectasis.
Apart from regular chest physiotherapy and postural drainage to help clearing mucus from bronchiectatic airways, inhalational and parenteral antibiotics have also been used to reduce the bacterial load in destroyed airways, thus controlling and preventing infective exacerbations. In recent years, accumulated evidence has suggested a central role of airway inflammation and immune dysregulation in the evolution of non-CF bronchiectasis. The classical type of airway inflammation is neutrophilic, with abundance of neutrophils in sputum, bronchoalveolar lavage fluid and bronchial biopsy from patients with non-CF bronchiectasis, even in clinically stable-state. The recruitment and trafficking of neutrophils to bronchiectatic airways are mediated via various pro-inflammatory cytokines like interleukin-1β (IL-1β), IL-8, tumour necrosis factor (TNF)-alpha and leukotriene B4 (LTB4). Investigators have also shown in an in vitro model that sputum from patients with non-CF bronchiectasis could stimulate IL-6 production from normal human bronchial epithelial cells, mediated via TNF-alpha. Recent data have suggested the involvement of Th17 immunity, in which Th17-polarized Cluster of Differentiation 4 (CD4) T cells can respond to bacteria (especially Pseudomonas aeruginosa) in bronchiectatic airways by elaboration of IL-17, leading to downstream IL-8 release from airway epithelial cells, neutrophil chemotaxis, mucus hypersecretion and formation of ectopic lymphoid follicles. This IL-17 driven pathway can further aggravate the vicious circle of key pathogenetic mechanisms in non-CF bronchiectasis. In previous studies, airway neutrophilic inflammation as indicated by sputum neutrophil count was inversely correlated with lung function (forced expiratory volume in 1 second, FEV1) and directly with duration of disease and severity (Bronchiectasis Severity Score, BSI) in stable non-CF bronchiectasis. Investigators have also demonstrated that sputum elastase, released from airway neutrophils, significantly correlated with 24-hour sputum volume, number of bronchiectatic lobes, percent predicted FEV1, and sputum leukocyte count in stable-state bronchiectasis. Patients with non-CF bronchiectasis harbouring Pseudomonas aeruginosa showed greater sputum neutrophilia and volume, with lower FEV1 and FEV1/forced vital capacity (FVC) ratio in previous studies from our group and others.
This study aims to investigate the extent of airway inflammation in non-CF bronchiectasis is indicated by sputum leukocyte density (primary outcome measure), pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, LTB4 and IL-17) and neutrophil elastase. Investigators hypothesize that 4-week treatment of roflumilast in stable-state non-CF bronchiectasis can result in: (1) reduction in sputum leukocyte density (primary hypothesis); (2) reduction in sputum pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, and IL-17) and LTB4; (3) reduction in sputum neutrophil elastase; (4) reduction in 24-h sputum volume; (5) no change in sputum bacterial colonization, load and microbiome.
Non-cystic Fibrosis Bronchiectasis
Queen Mary Hospital
The University of Hong Kong
Published on BioPortfolio: 2018-02-14T18:30:15-0500
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An autosomal recessive genetic disease of the EXOCRINE GLANDS. It is caused by mutations in the gene encoding the CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR expressed in several organs including the LUNG, the PANCREAS, the BILIARY SYSTEM, and the SWEAT GLANDS. Cystic fibrosis is characterized by epithelial secretory dysfunction associated with ductal obstruction resulting in AIRWAY OBSTRUCTION; chronic RESPIRATORY INFECTIONS; PANCREATIC INSUFFICIENCY; maldigestion; salt depletion; and HEAT PROSTRATION.
A chloride channel that regulates secretion in many exocrine tissues. Abnormalities in the CFTR gene have been shown to cause cystic fibrosis. (Hum Genet 1994;93(4):364-8)
A rehabilitation therapy for removal of copious mucus secretion from the lung of patients with diseases such as CHRONIC BRONCHITIS; BRONCHIECTASIS; PULMONARY ABSCESS; or CYSTIC FIBROSIS. The patient's head is placed in a downward incline (so the TRACHEA is inferior to the affected area) for 15- to 20-minute sessions.
A strain of mice widely studied as a model for cystic fibrosis. These mice are generated from embryonic stem cells in which the CFTR (cystic fibrosis transmembrane conductance regulator) gene is inactivated by gene targeting. As a result, all mice have one copy of this altered gene in all their tissues. Mice homozygous for the disrupted gene exhibit many features common to young cystic fibrosis patients, including failure to thrive, meconium ileus, and alteration of mucous and serous glands.
Irreversible FIBROSIS of the submucosal tissue of the MOUTH.
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