Abstract
BackgroundChronic 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/DesignTWICS 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.DiscussionThe 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 registrationCurrent Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0782-2) contains supplementary material, which is available to authorized users.
Highlights
Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs
Inhaled corticosteroids are beneficial in COPD, the airway inflammation in COPD is relatively insensitive to their anti-inflammatory effects even at high doses [12,13,14]
COPD is a common disease associated with high morbidity, mortality, and health-care costs despite the widespread use of inhaled corticosteroids
Summary
COPD is a common disease associated with high morbidity, mortality, and health-care costs despite the widespread use of inhaled corticosteroids. Pharmacokinetic modelling demonstrates that patients receiving ‘low dose’ theophylline will not achieve toxic levels of theophylline following the usual loading dose of aminophylline, because their baseline serum theophylline concentrations will vary between 1 and 5 mg/l; and after the loading dose of aminophylline, serum theophylline will remain within the conventional bronchodilating interval of 10–20 mg/l This is clinically important as the attending physician will not be aware whether a TWICS participant is on theophylline or placebo, and the modelling confirms that an aminophylline infusion can be safely administered if thought by the attending physician to be clinically indicated.
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