Title: INNOVATIVE USE OF ANTIBIOTICS IN THE PREVENTION OF EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Funder: Department of Health and Social Care

Abstract: AIMS and OBJECTIVES.The over-arching aim of this programme is to develop novel cost-effective approaches to the use of antibiotics in COPD, with the aim of reducing the considerable burden and health-care costs associated with this prevalent and devastating condition. BACKGROUND. COPD causes considerable morbidity, mortality and cost, much of it through exacerbations. Preventing exacerbations is important and current therapies are incompletely effective. Bacterial infection is important in COPD pathogenesis, though there is little evidence for use of long term antiobiotics. Incomplete recovery is also common after exacerbation, though it is not kown if targeted early retreatment is effective. RESEARCH PLANS. Our programme is made up of 6 inter-related Work Packages (WPs). WP1 addresses the use of long and short term antibiotics in COPD by analysing data from the THIN primary care database. WP2 is a development study in which four different antibiotic regimes are evaluated against placebo for their ability to reduce airway bacteria, with respect to cost, side-effects and patient outcomes. The regimes selected include daily amoxicillin, pulsed moxifloxacin, regular azithromycin and a fourth regime selected as the most common in existing practice from WP1.The most successful regime from WP2 will be examined in WP3 as a robust randomised trial in primary care, for the ability to prevent COPD exacerbations. An alternative approach to continuous treatment with antibiotic is to target re-treatment at patients demonstrating incomplete recovery after a first event, with the aim of preventing second events and a randomised trial of this approach in high-risk patients will form WP4. WP5 will assess the health-economic implications of the two strategies evaluated in WP3 and WP4, compared to current practice (WP1) thus providing key assessments applicable to the wider role out of successful findings. WP6 is concerned with patient adherence and will link with WP2 and WP3 such that factors determining adherence to long-term antibiotics in COPD can be assessed and addressed when new approaches are introduced into clinical care. RESEARCH TEAM. We are a collaboration of professionals from a variety of backgrounds, working together to assess the role of antibiotics for the benefit of patients and the health-service. From the start, and throughout the proposal, we have close patient representation, to ensure that the views and opinions of patients and their carers are considered and addressed. The team is led by Prof Wedzicha, UCL Medical School/Royal Free NHS Trust. She is supported by experts in studies of COPD, microbiology, epidemiology, primary care, clinical trials, statistics, adherence to medication, economics and health-services management. PROGRAMME MANAGEMENT.The programme will be overseen by a Steering Committee (SC) and each WP will be led by a specific member of the SC. A programme coordinator will be appointed and a Data Monitoring Committee will be convened for WP3. RESEARCH ENVIRONMENT. The research environment is key to the success of our collaboration. Primary care studies (WP2 and WP3) will be conducted through the robust MRC GP Research Framework network and PRIMENT. Studies in secondary care will be performed from large hospitals in London and Liverpool. Statistics are led from an MRC Unit in Cambridge and economic analysis from the London School of Economics. Other applicants including those examining adherence and the THIN database work with us at UCL and the application includes the Director of Clinical Service Improvement and previous acting Chief Executive of our Trust. ANTICIPATED OUTPUTS, OUTCOMES and IMPACT. The overall outcome will be validated novel methods of antibiotic therapy in COPD that are acceptable to patients and cost-effective to the NHS. Specifically, we aim to assess the role and value of antibiotics in stable COPD and targeted re-treatment at reducing exacerbation frequency. The impact for patients and the wider NHS will be considerable. The results of this programme can be implemented early after end of programme as all the antibiotics studied are available on prescription. PUBLIC INVOLVEMENT. We have and continue to develop close working links with our local patient groups, especially the Camden branch of the Breathe Easy group. The chair of this group has agreed to act as the patient representative on our steering group, and has already held focus groups which have informed the development of this proposal. ETHICAL IMPLICATIONS. This programme will require review by our local Ethics Committee. We do not anticipate problems in securing ethical approval. JUSTIFICATION FOR RESOURCES. Resources are requested for both existing senior staff and research staff including programme coordinator, clinical research fellows, research assistants, MRC GPRF costs, web based data management system, travel and other consumables. NHS Service costs are included.

Lay abstract: This programme of research concerns chronic obstructive pulmonary disease (COPD): a common and important lung condition that causes a great deal of ill-health, poor quality of life, death and cost to the health-services in the UK and world-wide. We will particularly focus on the role of antibiotics in COPD. Antibiotics are useful during acute flare-ups of COPD, called ‘exacerbations’, but have not been widely used at other times following research performed in the 1960s which at that time showed few benefits. More recently, new ways of using antibiotics have been developed, and new drugs too, and it may be that using these antibiotics can improve the health of patients with COPD, at the same time as reducing costs to the health services. Specifically, we aim to: 1. Assess the pattern of use of antibiotics in COPD in the UK, using a large database collected by General Practitioners. 2. Perform a small-scale test study to see which way of using antibiotics has the greatest effect on lung bacteria. We will test a variety of approaches including older regimes, newer regimes, and any regimes found to be common in our database survey. 3. We will then select the best regime and rigorously test the ability of this antibiotic to prevent exacerbation of COPD. 4. As an alternative approach, we will rigorously investigate the ability of a second course of antibiotics at the time of an exacerbation, in patients who have not completely recovered, to prevent the complication of a second exacerbation. 5. These two approaches will be compared in terms of their costs and benefits to patients and the NHS, by experienced Health-Economists. 6. Finally, we will explore the factors that concern patients regarding antibiotics, so that when we come to recommend treatment we will do this in a way that means patients will be more likely to take the treatment long term. In this way, we will evaluate new ways to use antibiotics in COPD, with results that can have a big impact both to patients living with COPD, and the NHS. To ensure success, we are a large team of health-care professionals, scientists and economists from a diverse range of backgrounds: all bringing individual expertise to address these key questions that could have a major impact on COPD in the UK and further afield. Importantly, we have the involvement of patients throughout the programme to ensure that the results are directly relevant to clinical care.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY