Roflumilast in Non-CF Bronchiectasis Study
Cuvinte cheie
Abstract
Descriere
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.
Datele
| Ultima verificare: | 08/31/2019 |
| Primul depus: | 01/25/2018 |
| Inscriere estimată trimisă: | 02/07/2018 |
| Prima postare: | 02/08/2018 |
| Ultima actualizare trimisă: | 09/29/2019 |
| Ultima actualizare postată: | 09/30/2019 |
| Data actuală de începere a studiului: | 05/09/2018 |
| Data estimată de finalizare primară: | 08/30/2019 |
| Data estimată de finalizare a studiului: | 08/30/2019 |
Stare sau boală
Intervenție / tratament
Drug: Oral roflumilast
Fază
Grupuri de brațe
| Braţ | Intervenție / tratament |
|---|---|
| Experimental: Oral roflumilast oral roflumilast 500 microgram daily for 4 weeks | Drug: Oral roflumilast Roflumilast, a phosphodiesterase 4 (PDE4) inhibitor is approved worldwide (including Hong Kong) for treatment of severe chronic obstructive pulmonary disease (COPD) with frequent exacerbations. Roflumilast has been shown to have anti-inflammatory effect in patients with COPD, with significant reduction of sputum absolute neutrophil count, IL-8 and neutrophil elastase compared with placebo treatment. Roflumilast can also improve the lung function parameters in patients with COPD and reduce the rate of moderate-to-severe exacerbations. |
Criterii de eligibilitate
| Vârste eligibile pentru studiu | 18 Years La 18 Years |
| Sexe eligibile pentru studiu | All |
| Acceptă voluntari sănătoși | da |
| Criterii | Inclusion Criteria: 1. Aged 18 years or above, male or female. 2. Never-smokers or those who have smoked less than 100 cigarettes in their lifetime. 3. Confirmed diagnosis of non-CF bronchiectasis based on high-resolution computed tomography (HRCT) scan. 4. Significant sputum production (≥ 10 ml per day). 5. In stable-state bronchiectasis with no change in regular medications (e.g. inhaled steroid, macrolide) or exacerbations in the past 3 months. 6. Written informed consent obtained. Exclusion Criteria: 1. Eversmokers (≥ 100 cigarettes in their lifetime). 2. Known chronic obstructive pulmonary disease or asthma. 3. Moderate to severe liver impairment (Child-Pugh B or C). 4. Known psychiatric illness with increased suicidal risks. 5. Body-mass index below 20 kg/m2. 6. Concomitant use of strong cytochrome P450 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin). 7. Patients who are hypersensitive to roflumilast or its constituents. 8. Pregnant or lactating women. |
Rezultat
Măsuri de rezultate primare
1. sputum leukocyte density [Reduction of sputum leukocyte density in 4 weeks]
