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Original Research: COPD |

Oral Low-dose Theophylline on Top of Inhaled Fluticasone-Salmeterol Does Not Reduce Exacerbations in Patients With Severe COPD: A Pilot Clinical Trial

Borja G. Cosío, MD, PhD; Hanaa Shafiek, MD, PhD; Amanda Iglesias, PhD; Aina Yanez, MD, PhD; Rocío Córdova, RN; Alexandre Palou, MD; Robert Rodriguez-Roisin, MD, PhD; Germán Peces-Barba, MD, PhD; Sergi Pascual, MD, PhD; Joaquim Gea, MD, PhD; Oriol Sibila, MD, PhD; Peter J. Barnes, MD, PhD; Alvar Agusti, MD, PhD
Author and Funding Information

FUNDING/SUPPORT: This study was supported, in part, by a grant from Fundación Mutua Madrileña and Ciberes.

aDepartment of Respiratory Medicine, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain

bResearch Unit, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain

cDepartment of Clinical Trials, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain

dChest Diseases Department, Alexandria University, Alexandria, Egypt

eServei de Pneumologia, Hospital Clínic de Barcelona, Barcelona, Spain

fHospital Universitario Fundación Jiménez Díaz, Madrid, Spain

gInstitut Hospital del Mar d’Investigacions Mediques, Barcelona, Spain

hHospital de la Santa Creu i Sant Pau, Barcelona, Spain

iNational Heart & Lung Institute, London, UK

jServei de Pneumologia, Hospital Clínic de Barcelona, Barcelona, Spain

kCIBERES, Madrid, Spain

CORRESPONDENCE TO: Borja G. Cosío, MD, PhD, Department of Respiratory Medicine, Hospital Universitario Son Espases, Carretera de Valldemossa 79, Palma de Mallorca, Baleares, Spain, 07010


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(1):123-130. doi:10.1016/j.chest.2016.04.011
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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

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