Background:

Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1–5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD.

Objective:

To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation.

Design:

A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial.

Setting:

The trial was conducted in 121 UK primary and secondary care sites.

Participants:

People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year.

Interventions:

Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status.

Primary outcome:

The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs.

Results:

A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV₁ was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV₁), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms.

Limitations:

A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment (n = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study.

Conclusion:

For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses.

Future work:

To promote consideration of the findings of this trial in national and international COPD guidelines.

Trial registration:

Current Controlled Trials ISRCTN27066620.

Funding:

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 37. See the NIHR Journals Library website for further project information.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 11/58/15. The contractual start date was in July 2013. The draft report began editorial review in April 2018 and was accepted for publication in November 2018. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Graham Burns reports personal fees from Boehringer Ingelheim GmbH (Ingelheim am Rhein, Germany), Teva Pharmaceutical Industries Ltd (Petah Tikva, Israel), Chiesi Farmaceutici SpA (Parma, Italy), Pfizer Inc. (New York City, NY, USA) and AstraZeneca plc (Cambridge, UK), and non-financial support from Chiesi and Boehringer Ingelheim, outside the submitted work. Rekha Chaudhuri reports personal fees from AstraZeneca, GlaxoSmithKline (GSK) plc (London, UK), Teva and Novartis International AG (Basel, Switzerland) for advisory board meetings, outside the submitted work. Anthony De Soyza reports grants and non-financial support from AstraZeneca and Chiesi, non-financial support from Boehringer Ingelheim, grants and personal fees from GSK, Bayer AG (Leverkusen, Germany) and Pfizer, and grants from Forest Laboratories (New York City, NY, USA)/Teva, outside the submitted work. He is also a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Elective and Emergency Specialist Care (EESC) Panel. Simon Gompertz reports personal fees from Pfizer and GSK, outside the submitted work. John Norrie reports grants from the NIHR HTA programme during the conduct of the study, was a member of the NIHR HTA Commissioning Board (2010–16) and is currently Deputy Chairperson of the NIHR HTA General Board (2016–present) and a NIHR Journals Library Editor (2014–present). Andrew Wilson reports grants from F. Hoffmann-La Roche (Basel, Switzerland), outside the submitted work. David Price reports grants and personal fees from Aerocrine AB (Stockholm, Sweden), AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan NV (Canonsburg, PA, USA), Mundipharma International Ltd (Cambridge, UK), Napp Pharmaceuticals Ltd (Cambridge, UK), Novartis, Pfizer, Teva, Theravance Biopharma (San Francisco, CA, USA) and Zentiva Group a.s. (Prague, Czech Republic); personal fees from Almirall SA (Barcelona, Spain), Amgen Inc. (Newbury Park, CA, USA), Cipla Ltd (Mumbai, India), GSK, Kyorin Pharmaceutical Co. Ltd (Tokyo, Japan), Merck Sharp & Dohme (Kenilworth, NJ, USA), Skyepharma Production SAS (Saint-Quentin-Fallavier, France); grants from AKL Research and Development Ltd (Stevenage, UK), the British Lung Foundation, the Respiratory Effectiveness Group and the UK NHS; and non-financial support from the NIHR Efficacy and Mechanism Evaluation and HTA programmes, outside the submitted work. He also reports stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals and owns 74% of the social enterprise Optimum Patient Care Ltd (Cambridge, UK, and Australia and Singapore) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore).