Award Title: A randomised, double-blind placebo controlled trial of the effectiveness of the beta-blocker bisoprolol in preventing exacerbations of chronic obstructive pulmonary disease
Funder: Chief Scientist Office, Scotland

Abstract: Chronic obstructive pulmonary disease (COPD) is a long term lung disease that slowly gets worse. Although COPD cannot be cured it can be treated. COPD used to be called chronic bronchitis/emphysema and is  strongly linked with smoking. It is common, with about 3 million people being affected in the UK, although only 1.2 million have received a COPD diagnosis. COPD is the fifth leading cause of death in the UK (causing 30,000 deaths each year). Sudden deteriorations, known as exacerbations or “flare ups” shorten life expectancy and reduce peoples’ ability to get on with their lives. COPD costs the NHS £1 billion a year, over half of which is taken up in treating flare ups._x000D_
Beta-blockers  are drugs widely used to treat blood pressure and heart disease. Non-heart specialists are very often unwilling to start people with COPD on beta-blockers because older beta-blockers had lung side effects. New evidence shows that newer beta-blockers targeting the heart, eg bisoprolol, are safe in COPD. There is now evidence that people with COPD who take beta-blockers are less likely to have flare ups even if they have no heart problems. This unexpected benefit of beta-blockers has not been tested in patients with COPD who are not known to need beta-blockers. A full randomised controlled trial is now needed to see if starting people with COPD on a beta-blocker reduces flare ups. The proposed trial builds on a COPD trial that has recruited 1560 people in 160 UK centres._x000D_
We will set up a randomised double blind placebo controlled trial to see if adding bisoprolol to usual COPD medicines reduces the number of COPD flare ups and makes patients feel better. We will recruit 1574 patients with COPD who have had flare ups recently (at least two in the last year). Potential participants will be identified from general practice and hospital chest clinics. We will recruit in 160 UK centres. Over 50% of subjects will be recruited from General Practice. Half of the 1574 subjects will take a bisoprolol tablet for a year. The other half will take an identical dummy pill. To work out the best dose of bisoprolol (and dummy pill) for each patient we will slowly build up the dose over 4 weeks whilst checking pulse and blood pressure. This is known to be safe._x000D_
Everyone will be seen 7 times: baseline, 1, 2, 3, 4, 26 and 52 weeks. The dose of bisoprolol (and the dummy pill) will be increased at the 1, 2 and 3 week visits._x000D_
At baseline, 26 and 52 weeks we will see the participants and use simple short questionnaires to count up the number of flare ups, hospital episodes, ability to get on with their lives, side effects and heart problems. Standard breathing tests will be performed to measure how well the lungs are working. We will also count how many times patients have seen a doctor/nurse to see if this reduces NHS costs. We will look at the GP records of those who leave the study early in case there are important reasons for this. _x000D_
Bisoprolol is cheap (4p/day) and if it works it will improve the lives people with COPD and reduce the costs of COPD to the NHS. Our group includes chest doctors, GPs, researchers with experience of running clinical trials as well as a person with COPD.

Lay Abstract: 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._x000D_
Setting: 160 primary and secondary care centres across our existing network that have recruited people with COPD into the TWICS trial._x000D_
Target population: 1574 patients diagnosed with COPD receiving usual NHS care at risk of exacerbating. At least 50% will be identified in primary care._x000D_
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._x000D_
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._x000D_
Health technology being assessed: The beta (ß1-selective) blocker bisoprolol, to be used in conjunction with usual NHS care and COPD treatment. _x000D_
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._x000D_
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._x000D_
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._x000D_
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._x000D_
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._x000D_
Recruitment will be for 36 months.. _x000D_
Expertise: An experienced multidisciplinary team comprising chest physicians, general practitioners, clinical trialists, a statistician, a health economist and a COPD patient.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: RESPIRATORY