A randomised, double-blind placebo controlled trial of the effectiveness of the beta-blocker bisoprolol in preventing exacerbations of chronic obstructive pulmonary disease

Design: A randomised double blind placebo controlled clinical trial to determine the clinical and cost effectiveness of adding once daily bisoprolol compared with placebo to reduce exacerbations in patients with COPD at risk of exacerbation. Setting: 160 primary and secondary care centres across our existing network that have recruited people with COPD into the TWICS trial. Target population: 1574 patients diagnosed with COPD receiving usual NHS care at risk of exacerbating. At least 50% will be identified in primary care. Inclusion criteria: 1) Diagnosed COPD (NICE definition: post bronchodilator FEV1<80% predicted, FEV1/FVC<0.7) receiving treatment as per local guidelines; and 2) A history of two or more COPD exacerbations in the previous year treated with oral corticosteroids and/or antibiotics. Exclusion criteria: current sole respiratory diagnosis of asthma, any asthma diagnosis before the age of 40 years, heart failure, use of beta-blockers or other heart rate limiting drugs, systolic blood pressure(BP)<100mmHg, heart rate(HR)<60/min, or heart block on ECG. Health technology being assessed: The beta (ß1-selective) blocker bisoprolol, to be used in conjunction with usual NHS care and COPD treatment. Allocation: Participants will be randomised 1:1 to once daily oral bisoprolol (maximum dose 5mg od) or placebo for a year. The intervention group will start oral bisoprolol at 1.25mg od with supervised weekly up-titration to maximal tolerated dose or 5mg a day dependent upon symptoms, heart rate, blood pressure and lung function. This dose will continue for the remaining 48 weeks of the trial. The control group will receive an identical oral placebo tablet od, similarly up-titrated and taken for 48 weeks. Measurement of costs and outcomes: The primary outcome will be the number of participant reported COPD exacerbations treated with antibiotics and/or OCS during the 1 year treatment period. The primary economic outcome measure will be incremental cost-per-exacerbation avoided and cost-per-QALY gained during the treatment period. All outcomes will be assessed blind at baseline, 26 and 52 weeks and will include: patient reported exacerbations, health care utilisation, disease-related health status (CAT test); health related quality of life (EQ-5D-3L); dyspnoea (BDI/TDI); lung function; mortality; adverse events/reactions; cardiac events. Permission to access GP records will be sought to identify exacerbations in those failing to complete the study. Sample size: The ECLIPSE study reported a mean (SD) exacerbation rate for such patients of 2.22/yr (1.86). With 669 subjects in each arm, the trial will be able to detect a clinically important 15% reduction in COPD exacerbations (i.e. from an average of 2.22 to 1.89) with 90% power at 5% significance level. Withdrawal from taking study drug is estimated at 15%, making total sample size 1574. Timetable: Study duration will be 60 months. Milestones are pre-funding: approvals; Months 1-6: Study set-up authorisations; Months 7-42: recruitment; Months 43-54 follow up; Months 55-60 data analysis, report writing. A 6 month internal pilot is included. Recruitment will be for 36 months.. Expertise: An experienced multidisciplinary team comprising chest physicians, general practitioners, clinical trialists, a statistician, a health economist and a COPD patient.