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


OBJECTIVE
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.


BACKGROUND
ClinicalTrials.gov; No.: NCT01599871; URL: www.clinicaltrials.gov.
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.
Borja G
BG
Cosío
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.
Hanaa
H
Shafiek
Research Unit, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain; CIBERES, Madrid, Spain.
Amanda
A
Iglesias
Department of Clinical Trials, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
Aina
A
Yanez
Department of Respiratory Medicine, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
Rocío
R
Córdova
Department of Respiratory Medicine, Hospital Universitario Son Espases-Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
Alexandre
A
Palou
Servei de Pneumologia, Hospital Clínic de Barcelona, Barcelona, Spain; CIBERES, Madrid, Spain.
Robert
R
Rodriguez-Roisin
Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; CIBERES, Madrid, Spain.
Germán
G
Peces-Barba
Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Spain; CIBERES, Madrid, Spain.
Sergi
S
Pascual
Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Spain; CIBERES, Madrid, Spain.
Joaquim
J
Gea
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; CIBERES, Madrid, Spain.
Oriol
O
Sibila
National Heart & Lung Institute, London, UK.
Peter J
PJ
Barnes
Servei de Pneumologia, Hospital Clínic de Barcelona, Barcelona, Spain; CIBERES, Madrid, Spain.
Alvar
A
Agusti
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001993:Bronchodilator Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy; D000067251:Symptom Flare Up; D013806:Theophylline / Q000008:administration & dosage*; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D015850:Interleukin-6; D016209:Interleukin-8; D013806:Theophylline
COPD; HDAC; airway inflammation; inflammation; steroid response; theophylline