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Trials. 2015 Jun 10;16:267. doi: 10.1186/s13063-015-0782-2.

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.

Author information

1
Respiratory Medicine, Chest Clinic C, Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, AB25 2ZN, UK. g.devereux@abdn.ac.uk.
2
Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. s.c.cotton@abdn.ac.uk.
3
Imperial College, National Heart & Lung Institute, Dovehouse Street, London, SW3 6LY, UK. p.j.barnes@imperial.ac.uk.
4
Institute of Health & Wellbeing, University of Glasgow, 1 Lilybank Gardens, Glasgow, G12 8RZ, UK. andrew.briggs@glasgow.ac.uk.
5
Department of Respiratory Medicine, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, UK. graham.burns@nuth.nhs.uk.
6
Gartnavel General Hospital, University of Glasgow, Glasgow, G12 0YN, UK. rekha.chaudhuri@ggc.scot.nhs.uk.
7
Division of Pharmacy & Pharmaceutical Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK. h.chrystyn@hud.ac.uk.
8
Aintree Chest Centre, University Hospital Aintree, Liverpool, L9 7AL, UK. lisa.davies@aintree.nhs.uk.
9
Medical School, University of Newcastle, Newcastle Upon Tyne, NE2 4HH, UK. anthony.de-soyza@newcastle.ac.uk.
10
Medical Statistics Team, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK. s.fielding@abdn.ac.uk.
11
Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. simon.gompertz@uhb.nhs.uk.
12
Centre of Academic Primary Care, University of Aberdeen, Aberdeen, AB25 2ZD, UK. j.haughney@abdn.ac.uk.
13
Medical Statistics Team, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK. a.j.lee@abdn.ac.uk.
14
Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. k.mccormack@abdn.ac.uk.
15
Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. g.mcpherson@abdn.ac.uk.
16
Cardiovascular and Respiratory Studies, Castle Hill Hospital, Hull, HU16 5JQ, UK. a.h.morice@hull.ac.uk.
17
Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. j.norrie@abdn.ac.uk.
18
Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. anita.sullivan@uhb.nhs.uk.
19
Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK. a.m.wilson@uea.ac.uk.
20
Centre of Academic Primary Care, University of Aberdeen, Aberdeen, AB25 2ZD, UK. david@respiratoryresearch.org.

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.

PMID:
26058585
PMCID:
PMC4465017
DOI:
10.1186/s13063-015-0782-2
[Indexed for MEDLINE]
Free PMC Article

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