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

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 (FEV

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 FEV

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 (

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

Chronic obstructive pulmonary disease (COPD) is a long-term lung disease that cannot be cured. The main symptom is shortness of breath on exertion. In the UK, about 1.2 million people have COPD. It is a major cause of death and costs the NHS > £1B a year. Sudden ‘flare-ups’ of symptoms often need emergency treatment, shorten life expectancy and reduce people’s ability to get on with their lives. Theophylline is a drug that has been around for decades. In the past, it was used in high doses to treat COPD by opening up airways. However, its benefits were limited and it often caused unpleasant side effects. High-dose theophylline has been replaced by drugs administered by inhalers, such as inhaled corticosteroids (ICSs). Recent work in the laboratory and in animal models suggests that, at low dose, theophylline could make ICSs work better in COPD with none of the side effects of high-dose theophylline. The Theophylline With Inhaled CorticoSteroid (TWICS) trial tested whether or not adding low-dose theophylline reduces flare-ups in people with COPD taking ICSs. A total of 1578 people with COPD from 121 centres all over the UK took part. Participants were randomly divided into two groups: one group took low-dose theophylline and the other took dummy placebo pills. Participants were asked to attend visits at 6 and 12 months. A total of 791 participants were prescribed low-dose theophylline and 787 were prescribed dummy placebo pills. Although not everyone took the tablets for a whole year, it was possible to count the number of flare-ups in 98% of those taking part. In total, there were 3430 flare-ups. On average, the people taking low-dose theophylline had 2.24 flare-ups and the people taking placebo had 2.23 flare-ups. Overall, the trial showed that, for people with COPD, taking low-dose theophylline on top of steroid inhalers makes no real difference.

Déclaration de conflit d'intérêts

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).