Borja G Cosío1, Hanaa Shafiek2, Amanda Iglesias3, Aina Yanez4, Rocío Córdova5, Alexandre Palou5, Robert Rodriguez-Roisin6, Germán Peces-Barba7, Sergi Pascual8, Joaquim Gea8, Oriol Sibila9, Peter J Barnes10, Alvar Agusti6. 1. Department of Respiratory Medicine, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain; CIBERES, Madrid, Spain. Electronic address: borja.cosio@ssib.es. 2. Department of Respiratory Medicine, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain; Chest Diseases Department, Alexandria University, Alexandria, Egypt. 3. Research Unit, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain; CIBERES, Madrid, Spain. 4. Department of Clinical Trials, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain. 5. Department of Respiratory Medicine, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain. 6. Servei de Pneumologia, Hospital Clínic de Barcelona, Barcelona, Spain; CIBERES, Madrid, Spain. 7. Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; CIBERES, Madrid, Spain. 8. Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Spain; CIBERES, Madrid, Spain. 9. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; CIBERES, Madrid, Spain. 10. National Heart & Lung Institute, London, UK.
Abstract
BACKGROUND: COPD is characterized by chronic inflammation. In vitro and ex vivo observations suggest that this inflammatory response is partially resistant to the effect of corticosteroids and that low-dose theophylline can restore this response via enhancement of histone deacetylase (HDAC) activity. Whether this occurs in vivo and what its potential clinical consequences are is unclear. OBJECTIVES: The objective of this trial was to determine whether low-dose theophylline on top of inhaled long-acting β2-agonists and inhaled corticosteroids (ICS) in patients with COPD (1) enhances HDAC activity and the antiinflammatory effects of ICS in vivo, (2) reduces the concentration of inflammatory markers, and (3) reduces exacerbation frequency. METHODS: In this prospective, double-blind, placebo-controlled clinical trial, we randomized patients with COPD (FEV1 < 50% predicted plus at least one hospitalization due to exacerbation in the previous year) toICS plus theophylline 100 mg bid or matched placebo. We determined the following at baseline and at the end of 52 weeks of follow-up: (1) HDAC activity in blood monocytes and sputum macrophages, (2) the concentration of several inflammatory markers (IL-8, IL-6, IL-1β, and tumor necrosis factor -α) in serum and sputum supernatant, and (3) the rates of exacerbations and adverse effects. RESULTS:Seventy patients wererandomized-36 to theophylline and 34 to placebo. HDAC activity and inflammatory marker levels were not different in the two arms either at baseline or after 52 weeks. Likewise, the rate of exacerbations during follow-up was similar in both groups. CONCLUSIONS: The combination of low-dose oral theophylline and ICS did not enhance the antiinflammatory properties of ICS in vivo or influence exacerbation rate. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01599871; URL: www.clinicaltrials.gov.
RCT Entities:
BACKGROUND:COPD is characterized by chronic inflammation. In vitro and ex vivo observations suggest that this inflammatory response is partially resistant to the effect of corticosteroids and that low-dose theophylline can restore this response via enhancement of histone deacetylase (HDAC) activity. Whether this occurs in vivo and what its potential clinical consequences are is unclear. OBJECTIVES: The objective of this trial was to determine whether low-dose theophylline on top of inhaled long-acting β2-agonists and inhaled corticosteroids (ICS) in patients with COPD (1) enhances HDAC activity and the antiinflammatory effects of ICS in vivo, (2) reduces the concentration of inflammatory markers, and (3) reduces exacerbation frequency. METHODS: In this prospective, double-blind, placebo-controlled clinical trial, we randomized patients with COPD (FEV1 < 50% predicted plus at least one hospitalization due to exacerbation in the previous year) to ICS plus theophylline 100 mg bid or matched placebo. We determined the following at baseline and at the end of 52 weeks of follow-up: (1) HDAC activity in blood monocytes and sputum macrophages, (2) the concentration of several inflammatory markers (IL-8, IL-6, IL-1β, and tumor necrosis factor -α) in serum and sputum supernatant, and (3) the rates of exacerbations and adverse effects. RESULTS: Seventy patients were randomized-36 to theophylline and 34 to placebo. HDAC activity and inflammatory marker levels were not different in the two arms either at baseline or after 52 weeks. Likewise, the rate of exacerbations during follow-up was similar in both groups. CONCLUSIONS: The combination of low-dose oral theophylline and ICS did not enhance the antiinflammatory properties of ICS in vivo or influence exacerbation rate. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01599871; URL: www.clinicaltrials.gov.
Authors: Graham Devereux; Seonaidh Cotton; Shona Fielding; Nicola McMeekin; Peter J Barnes; Andrew Briggs; Graham Burns; Rekha Chaudhuri; Henry Chrystyn; Lisa Davies; Anthony De Soyza; Simon Gompertz; John Haughney; Karen Innes; Joanna Kaniewska; Amanda Lee; Alyn Morice; John Norrie; Anita Sullivan; Andrew Wilson; David Price Journal: JAMA Date: 2018-10-16 Impact factor: 56.272