Low-dose oral theophylline combined with inhaled corticosteroids for people with chronic obstructive pulmonary disease and high risk of exacerbations: a RCT

Graham Devereux, Seonaidh Cotton, Shona Fielding, Nicola McMeekin, Peter J. Barnes, Andy Briggs, Graham Burns, Rekha Chaudhuri, Henry Chrystyn, Lisa Davies, Anthony De Soyza, Simon Gompertz, John Haughney, Karen Innes, Joanna Kaniewska, Amanda Lee, Alyn Morice, John Norrie, Anita Sullivan, Andrew WilsonDavid Price

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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.

Original languageEnglish
Pages (from-to)1-146
Number of pages146
JournalHealth technology assessment (Winchester, England)
Issue number37
Early online date31 Jul 2019
Publication statusPublished - 31 Jul 2019

Bibliographical note

We would like to thank all the participants who took part in the trial. We are grateful to all the staff at recruitment sites who facilitated identification, recruitment and follow-up of study participants (listed below). We are also grateful to other general practices and organisations that acted as PICs for the trial and practices that provided outcome data for trial participants who were unable to attend for follow-up. We could not have completed the trial without the ongoing support of local and primary care research networks:
-NHS Research Scotland Primary Care Network (formerly Scottish Primary Care Research Network) – Amanda Cardy, Samantha Holden, Tracy Ibbotson, Yvonne McIlvenna, Marie Pitkethly, Janice Reid, Kim Stringer
-North of England Commissioning Support (NECS) – Jeanette Dixon, Jill Ducker, Shona Haining, Gillian Johnson, Rachel Nixon, Norah Phipps, Cheryl Rigg
- NIHR CRN South West Peninsula – Cate Atkins, Helen Clough, Tania Crabb, Patricia Hollway, Sara McNamara, Lisa Treeby, Lorraine Underwood
- NIHR CRN Eastern – Lynne Baker, Brenda DeBoys, Kim Fell, Fenglin Guo, Emily Ikelle, Helen Jung, Heather Leishman, Rachel Lister, Lynn Mather, Cristina Page, Barbara Stewart
- NIHR CRN Wessex Primary Care – Christine Brown
- NIHR CRN Yorkshire and Humber – Carla Bratten
-NIHR CRN North Thames – Mandy Austin, Carole Bartlett, Carol Keel, Helen McIver, Lucy Peppiatt.
We thank Nadia Lewis-Burke for invaluable assistance in data checking. We are grateful to Georgia Mannion-Krase, Andrea Fraser and Lana Mitchell for their secretarial and data co-ordination support. We are grateful to Kirsty McCormack for her help and advice in developing the grant proposal. We thank Gladys McPherson, Mark Forrest and the programming team in CHaRT for developing and maintaining the trial website. We also thank Juliette Snow, Ruth Speedie and Rachel West for their help with contracting, and Louise Cotterell and Glenys Milton for their help in managing the budget.
We are grateful for the guidance and support of the TSC (chairperson: Bill McNee; independent members: Matt Sydes, Mike Thomas, Alister Laird, Marion Middler) and the DMC chairperson: Hilary Pinnock; independent members: Chris Weir, Michael Steiner). We are also grateful to Bev Wears (British Lung Foundation) and Jacqueline Waters for helpful comments on early drafts of the trial documentation.
We acknowledge Napp Pharmaceuticals Ltd for providing the trial drug (Uniphyllin, 200-mg modifiedrelease tablets) free of charge for use in the trial.
The Health Services Research Unit and the Health Economics Research Unit are core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate.


  • COPD


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