title: 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.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.
authors.affiliation: Respiratory Medicine, Chest Clinic C, Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, AB25 2ZN, UK. g.devereux@abdn.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Devereux
authors.affiliation: Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. s.c.cotton@abdn.ac.uk.
authors.forename: Seonaidh
authors.initials: S
authors.lastname: Cotton
authors.affiliation: Imperial College, National Heart & Lung Institute, Dovehouse Street, London, SW3 6LY, UK. p.j.barnes@imperial.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Barnes
authors.affiliation: Institute of Health & Wellbeing, University of Glasgow, 1 Lilybank Gardens, Glasgow, G12 8RZ, UK. andrew.briggs@glasgow.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Briggs
authors.affiliation: Department of Respiratory Medicine, Royal Victoria Infirmary, Newcastle Upon Tyne, NE1 4LP, UK. graham.burns@nuth.nhs.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Burns
authors.affiliation: Gartnavel General Hospital, University of Glasgow, Glasgow, G12 0YN, UK. rekha.chaudhuri@ggc.scot.nhs.uk.
authors.forename: Rekha
authors.initials: R
authors.lastname: Chaudhuri
authors.affiliation: Division of Pharmacy & Pharmaceutical Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK. h.chrystyn@hud.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Chrystyn
authors.affiliation: Aintree Chest Centre, University Hospital Aintree, Liverpool, L9 7AL, UK. lisa.davies@aintree.nhs.uk.
authors.forename: Lisa
authors.initials: L
authors.lastname: Davies
authors.affiliation: Medical School, University of Newcastle, Newcastle Upon Tyne, NE2 4HH, UK. anthony.de-soyza@newcastle.ac.uk.
authors.forename: Anthony
authors.initials: A
authors.lastname: De Soyza
authors.affiliation: Medical Statistics Team, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK. s.fielding@abdn.ac.uk.
authors.forename: Shona
authors.initials: S
authors.lastname: Fielding
authors.affiliation: Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. simon.gompertz@uhb.nhs.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Gompertz
authors.affiliation: Centre of Academic Primary Care, University of Aberdeen, Aberdeen, AB25 2ZD, UK. j.haughney@abdn.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Haughney
authors.affiliation: Medical Statistics Team, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK. a.j.lee@abdn.ac.uk.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lee
authors.affiliation: Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. k.mccormack@abdn.ac.uk.
authors.forename: Kirsty
authors.initials: K
authors.lastname: McCormack
authors.affiliation: Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. g.mcpherson@abdn.ac.uk.
authors.forename: Gladys
authors.initials: G
authors.lastname: McPherson
authors.affiliation: Cardiovascular and Respiratory Studies, Castle Hill Hospital, Hull, HU16 5JQ, UK. a.h.morice@hull.ac.uk.
authors.forename: Alyn
authors.initials: A
authors.lastname: Morice
authors.affiliation: Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen, Aberdeen, AB25 2ZN, UK. j.norrie@abdn.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Norrie
authors.affiliation: Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK. anita.sullivan@uhb.nhs.uk.
authors.forename: Anita
authors.initials: A
authors.lastname: Sullivan
authors.affiliation: Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK. a.m.wilson@uea.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Centre of Academic Primary Care, University of Aberdeen, Aberdeen, AB25 2ZD, UK. david@respiratoryresearch.org.
authors.forename: David
authors.initials: D
authors.lastname: Price
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000191:economics; D002985:Clinical Protocols; D003362:Cost-Benefit Analysis; D018450:Disease Progression; D004311:Double-Blind Method; D016527:Drug Costs; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000191:economics / Q000503:physiopathology; D012107:Research Design; D013806:Theophylline / Q000008:administration & dosage* / Q000009:adverse effects / Q000191:economics; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D014797:Vital Capacity
chemical_list: D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D001993:Bronchodilator Agents; D013806:Theophylline