Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial

Trials, Jun 2015

Background Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that ‘low dose’ theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of ‘low dose’ theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. Method/Design TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either ‘low dose’ theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1–5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. Discussion The demonstration that ‘low dose’ theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. Trial registration Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.

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Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial

Devereux et al. Trials Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial Graham Devereux 0 Seonaidh Cotton 2 Peter Barnes 1 Andrew Briggs 7 Graham Burns 6 Rekha Chaudhuri 5 Henry Chrystyn 4 Lisa Davies 9 Anthony De Soyza 8 Shona Fielding 3 Simon Gompertz 12 John Haughney 13 Amanda J. Lee 3 Kirsty McCormack 2 Gladys McPherson 2 Alyn Morice 10 John Norrie 2 Anita Sullivan 12 Andrew Wilson 11 David Price 13 0 Respiratory Medicine, Chest Clinic C, Aberdeen Royal Infirmary, University of Aberdeen , Aberdeen AB25 2ZN , UK 1 Imperial College, National Heart & Lung Institute , Dovehouse Street, London SW3 6LY , UK 2 Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen , Aberdeen AB25 2ZN , UK 3 Medical Statistics Team, Division of Applied Health Sciences, University of Aberdeen , Aberdeen AB25 2ZD , UK 4 Division of Pharmacy & Pharmaceutical Sciences, University of Huddersfield , Huddersfield HD1 3DH , UK 5 Gartnavel General Hospital, University of Glasgow , Glasgow G12 0YN , UK 6 Department of Respiratory Medicine, Royal Victoria Infirmary , Newcastle Upon Tyne NE1 4LP , UK 7 Institute of Health & Wellbeing, University of Glasgow , 1 Lilybank Gardens, Glasgow G12 8RZ , UK 8 Medical School, University of Newcastle , Newcastle Upon Tyne NE2 4HH , UK 9 Aintree Chest Centre, University Hospital Aintree , Liverpool L9 7AL , UK 10 Cardiovascular and Respiratory Studies, Castle Hill Hospital , Hull HU16 5JQ , UK 11 Department of Medicine, Norwich Medical School, University of East Anglia , Norwich NR4 7TJ , UK 12 Queen Elizabeth Hospital Birmingham , Birmingham B15 2WB , UK 13 Centre of Academic Primary Care, University of Aberdeen , Aberdeen AB25 2ZD , UK Background: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. Method/Design: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. (Continued on next page) - (Continued from previous page) Discussion: The demonstration that ‘low dose’ theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. Trial registration: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014. Background Chronic obstructive pulmonary disease (COPD) is a lung disease characterised by progressive airflow obstruction that is not fully reversible and does not change markedly over several months [1]. COPD is common, is caused predominantly by cigarette smoking, and is usually diagnosed from the age of 50 years onwards. In the UK, there arenearly one million diagnosed cases, and COPD accounts for 5–6 % of all deaths (about 28,000 deaths in 2012) [2]. COPD is typically associated with increasing breathlessness on exertion, disability, work absence, premature retire (...truncated)


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Graham Devereux, Seonaidh Cotton, Peter Barnes, Andrew Briggs, Graham Burns, Rekha Chaudhuri, Henry Chrystyn, Lisa Davies, Anthony De Soyza, Shona Fielding, Simon Gompertz, John Haughney, Amanda Lee, Kirsty McCormack, Gladys McPherson, Alyn Morice, John Norrie, Anita Sullivan, Andrew Wilson, David Price. Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial, Trials, 2015, pp. 267, 16, DOI: 10.1186/s13063-015-0782-2