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Original Investigation
October 16, 2018

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Respiratory Medicine, Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, United Kingdom
  • 2Liverpool School of Tropical Medicine, Liverpool, United Kingdom
  • 3Aintree Chest Centre, University Hospital Aintree, Liverpool, United Kingdom
  • 4Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, United Kingdom
  • 5Medical Statistics Team, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom
  • 6Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
  • 7National Heart and Lung Institute, Imperial College, London, United Kingdom
  • 8Department of Respiratory Medicine, Royal Victoria Infirmary, Newcastle, United Kingdom
  • 9Asthma/COPD Clinical Research Centre, Gartnavel General Hospital, University of Glasgow, Glasgow, United Kingdom
  • 10Inhalation Consultancy Ltd, Tarn House, Yeadon, Leeds, United Kingdom
  • 11Medical School, Newcastle University, Newcastle Upon Tyne, United Kingdom
  • 12Respiratory Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
  • 13Department of Academic Primary Care, University of Aberdeen, Aberdeen, United Kingdom
  • 14Department of Cardiovascular and Respiratory Studies, Castle Hill Hospital, Hull, United Kingdom
  • 15Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
  • 16Observational and Pragmatic Research Institute, Paya Lebar Square, Singapore
JAMA. 2018;320(15):1548-1559. doi:10.1001/jama.2018.14432
Key Points

Question  Does low-dose theophylline reduce the risk of exacerbation in patients with chronic obstructive pulmonary disease (COPD) when added to inhaled corticosteroids?

Findings  In this pragmatic randomized clinical trial that included 1567 participants with COPD treated with inhaled corticosteroids, the addition of low-dose theophylline did not significantly reduce the mean number of exacerbations compared with placebo over a 1-year period (2.24 vs 2.23).

Meaning  The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for prevention of COPD exacerbations.


Importance  Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD.

Objective  To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD.

Design, Setting, and Participants  The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites.

Interventions  Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787).

Main Outcomes and Measures  The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period.

Results  Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, −0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%).

Conclusions and Relevance  Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations.

Trial Registration  isrctn.org Identifier: ISRCTN27066620