The main objective of the study is to determine the effects of low-dose oral theophylline added to combination treatment with long-acting β-agonist (LABA) and inhaled corticosteroid (ICS) in patients with severe Chronic Obstructive Pulmonary Disease (COPD) on the rate of exacerbations defined as increase of symptoms that requires a change of medication (antibiotics and/or systemic glucocorticoid) or hospitalisation.

DESIGN: Phase III multicenter, randomized, placebo-controlled, double blind, parallel, prospective study. Patient will be recruited during an hospitalisation due to COPD exacerbation and randomised at the time of discharge to receive theophylline 100 mg or placebo on top of combination therapy with inhaled corticosteroids and long-acting beta agonist. The rate of exacerbations will be determined every three months up to one year follow-up. Cl inic visits: every 3 months (total number of clinic visits = 4). In each of them, the following information will be obtained:

• Number/severity of exacerbations or hospitalisation since last clinic visit

• Compliance and side effects

• Blood sample

• Plasma levels of theophylline

• Sputum (induced)

• MMRC

• SGRQ

• Forced spirometry + inspiratory capacity

  - At the beginning and at the end of the study

• 6MWT

• BMI

• BODE

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the study.
• Ability to understand study procedures and to comply with them for the entire length of the study.
• Any gender. No contraception is required neither pregnancy expected in the range of age
• Age > 45 years
• Smoking history > 10 pack-years (current or ex-smokers)
• Clinical diagnosis of COPD
• Presence of severe airflow obstruction on forced spirometry (FEV1/FVC < 0.7 and post-BD FEV1 < 50% of reference value) staged as GOLD III or IV
• Diagnosis of COPD exacerbation on discharge.

Exclusion Criteria:

• Presence or history of other chronic respiratory diseases (asthma, bronchiectasis, TB lesions)
• Cancer
• Heart failure
• Pregnancy, or risk of pregnancy
• Other inflammatory diseases
• Previous treatment with theophylline
• For drug studies: allergy/sensitivity to study drugs or their ingredients.
• Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.