Title: STABILISE: a multicentre, double blind, randomised, parallel group, superiority trial to investigate the use of BCG vaccine in altering immune response and exacerbation in chronic obstructive pulmonary disease (COPD)
Funder: Medical Research Council

Abstract: The vaccine for tuberculosis (Bacillus Calmette–Guérin, BCG) has been in use to prevent this disease for over 100 years. More recently studies have shown that in both adults and children, giving this vaccine can result in other benefits, including helpful changes within the immune system that can protect against many other infections, and may prevent hospital admissions in older people as a result. Studies on these effects, sometimes referred to as “trained immunity” have been small, and we do not know if the effect is true until properly designed studies have been done. The main benefit of BCG seems to be on rates of chest infections, which are more common in people who have a lung disease already, such as chronic obstructive pulmonary disease (COPD). Flare ups of lung disease are usually called exacerbations, and are mainly (but not always) due to infection. Preventing exacerbations in people with lung disease is particularly important because frequent infections can cause lung disease to progress, and every time an infection happens quality of life may get worse. Using the BCG vaccine as a means of prevention in such people could therefore be helpful for long term health by breaking the vicious cycle of recurrent exacerbations and progressive lung pathology . The STABILISE trial will enrol 804 patients who have COPD, and who have had at least two exacerbation in the last 12 months. We will recruit in hospitals and GP practices. Half of the patients will receive the vaccine, and half will receive a placebo. Patients will then be followed up for a year and their rate of exacerbations compared. We will also study symptoms, quality of life and hospital admissions in the two groups. To understand how the vaccine works, we will send tests at enrolment, and at 1 year to look at the function of the immune system. Patients will also have the option to send tests at the time of exacerbation from their own home - these will look for the presence of viruses, bacteria and chemicals within the immune system that will help to explain the cause of the flare up and why the vaccine works. These tests are simple to perform, and comprise a fingerprick blood test, phlegm sample and throat swab, which patients will be shown how to do by the research team. The study has been designed to ensure that we can detect a reduction of 20% in exacerbations/patient/year between vaccinated and unvaccinated participants, and will control for factors such as age and prior BCG vaccination in childhood by balancing these factors between the arms of the trial. Alongside the trial we will conduct interviews with patients to ensure that this kind of treatment would be acceptable in real-life, exploring attitudes to vaccines as we do so. The trial team comprises doctors who work in respiratory medicine, infectious disease and microbiology, as well as scientists who study the immune system, a trials unit, statistician, health economist and medical sociologist. We will involve patients throughout the study, looking at trial materials and results, and helping us to share them with the patient community.

Lay abstract: Research question: Does BCG vaccination reduce exacerbations in patients with COPD? Background: Chronic obstructive pulmonary disease (COPD) is an airways diseases characterised by fixed airflow obstruction, alongside typical clinical history and radiology. It often overlaps with asthma or bronchiectasis. COPD affects almost 2m people in the UK. BCG vaccine has been used to prevent tuberculosis (TB) for over 70 years, however there is growing evidence that its protective effects may be broader via effects on trained immunity. Our hypothesis is that the vaccine will reduce infectious exacerbations of airways disease, and that there may be a greater effect for viral driven events. Aims and objectives 1. Determine whether BCG reduces rates of respiratory exacerbations at 12 months in patients who have a clinical diagnosis of COPD, and a history of 2 exacerbations in the preceding year 2. Compare the rate of hospitalisations for infective exacerbations, quality of life (QOL) and number of days of antibiotic and steroid therapy in the follow up period between intervention and placebo arms 3. Explore the immunological basis by which BCG may confer non-specific protection against infection 4. Determine acceptability of BCG vaccine for this purpose Methods: STABILISE is an individually randomised, multicentre, double blind, two arm, parallel group, clinical trial testing the efficacy of BCG vaccine to reduce moderate-severe exacerbations of COPD against placebo over 12 months. There is an internal pilot phase and a process evaluation. It will recruit 804 patients with COPD from secondary and primary care. Exploratory work to determine the mechanism by which BCG has its effects will be conducted through 3 tiers of testing; tier 1 is in all patients and assesses humoral immunity via dried blood spots (DBS). Tier 2 involves more detailed assessment of such using venepuncture. Tier 3 captures microbiological and immunological information at the start of exacerbations via patient submitted sputum, viral swab and DBS samples sent to the central lab by post. Follow up occurs at 12 months in person for all tiers, with 1 and 3 month visits for tier 2 only. All other data is collected remotely or submitted directly by patients. An embedded qualitative study will determine acceptability and suggest means of enhancing vaccine uptake, if effective. Timelines: STABILISE patients are being recruited over 2 years and followed up for 1 year, such that the overall study takes 4 years, accounting for set up times and analysis Anticipated impact and dissemination: Dissemination will occur through conferences and publications, as well as through the trial PPI group and a regular newsletter. Impact is anticipated through changes in guidance on vaccination schedule for airways disease patients

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY