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, Seonaidh Cotton, Peter Barnes, Andrew Briggs, Graham Burns, Rekha Chaudhuri, Henry Chrystyn, Lisa Davies, Anthony De Soyza, Shona Fielding, Simon Gompertz, John Andrew Francis Haughney, Amanda J Lee, Kirsty McCormack, Gladys McPherson, Alyn Morice, John Norrie, Anita Sullivan, Andrew Wilson, David Price

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number267
JournalTrials
Volume16
DOIs
Publication statusPublished - 10 Jun 2015

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Theophylline
Chronic Obstructive Pulmonary Disease
Adrenal Cortex Hormones
Randomized Controlled Trials
Placebos
Smoke
Ideal Body Weight
Anti-Bacterial Agents
Secondary Care
Bronchodilator Agents
Vital Capacity
Forced Expiratory Volume
Random Allocation
Health Personnel
Health Care Costs
Tablets
Cost-Benefit Analysis
Disease Progression
Primary Health Care
Anti-Inflammatory Agents

Keywords

  • COPD
  • theophylline
  • inhaled corticosteroids
  • exacerbation
  • randomised controlled trial

Cite this

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, Graham; Cotton, Seonaidh; Barnes, Peter; Briggs, Andrew; Burns, Graham; Chaudhuri, Rekha; Chrystyn, Henry; Davies, Lisa; De Soyza, Anthony; Fielding, Shona; Gompertz, Simon; Haughney, John Andrew Francis; Lee, Amanda J; McCormack, Kirsty; McPherson, Gladys; Morice, Alyn; Norrie, John; Sullivan, Anita; Wilson, Andrew; Price, David.

In: Trials, Vol. 16, 267, 10.06.2015.

Research output: Contribution to journalArticle

Devereux, Graham ; Cotton, Seonaidh ; Barnes, Peter ; Briggs, Andrew ; Burns, Graham ; Chaudhuri, Rekha ; Chrystyn, Henry ; Davies, Lisa ; De Soyza, Anthony ; Fielding, Shona ; Gompertz, Simon ; Haughney, John Andrew Francis ; Lee, Amanda J ; McCormack, Kirsty ; McPherson, Gladys ; Morice, Alyn ; Norrie, John ; Sullivan, Anita ; Wilson, Andrew ; Price, David. / 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. In: Trials. 2015 ; Vol. 16.
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abstract = "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.",
keywords = "COPD, theophylline, inhaled corticosteroids, exacerbation, randomised controlled trial",
author = "Graham Devereux and Seonaidh Cotton and Peter Barnes and Andrew Briggs and Graham Burns and Rekha Chaudhuri and Henry Chrystyn and Lisa Davies and {De Soyza}, Anthony and Shona Fielding and Simon Gompertz and Haughney, {John Andrew Francis} and Lee, {Amanda J} and Kirsty McCormack and Gladys McPherson and Alyn Morice and John Norrie and Anita Sullivan and Andrew Wilson and David Price",
note = "Acknowledgements This project is funded by the National Institute for Health Research Health Technology Assessment Programme (project number 11/58/15). The Uniphyllin MR tablets have been provided gratis by Napp Pharmaceuticals Limited. As a courtesy, Napp Pharmaceuticals Limited will be provided with a copy of any manuscript prior to submission. We would like to acknowledge Nicholas Locantore for providing us with detailed data from the ECLIPSE study.",
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volume = "16",
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TY - JOUR

T1 - Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease

T2 - study protocol for a randomised controlled trial

AU - Devereux, Graham

AU - Cotton, Seonaidh

AU - Barnes, Peter

AU - Briggs, Andrew

AU - Burns, Graham

AU - Chaudhuri, Rekha

AU - Chrystyn, Henry

AU - Davies, Lisa

AU - De Soyza, Anthony

AU - Fielding, Shona

AU - Gompertz, Simon

AU - Haughney, John Andrew Francis

AU - Lee, Amanda J

AU - McCormack, Kirsty

AU - McPherson, Gladys

AU - Morice, Alyn

AU - Norrie, John

AU - Sullivan, Anita

AU - Wilson, Andrew

AU - Price, David

N1 - Acknowledgements This project is funded by the National Institute for Health Research Health Technology Assessment Programme (project number 11/58/15). The Uniphyllin MR tablets have been provided gratis by Napp Pharmaceuticals Limited. As a courtesy, Napp Pharmaceuticals Limited will be provided with a copy of any manuscript prior to submission. We would like to acknowledge Nicholas Locantore for providing us with detailed data from the ECLIPSE study.

PY - 2015/6/10

Y1 - 2015/6/10

N2 - 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.

AB - 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.

KW - COPD

KW - theophylline

KW - inhaled corticosteroids

KW - exacerbation

KW - randomised controlled trial

U2 - 10.1186/s13063-015-0782-2

DO - 10.1186/s13063-015-0782-2

M3 - Article

VL - 16

JO - Trials

JF - Trials

SN - 1745-6215

M1 - 267

ER -