Title: Dual Bronchodilators In Bronchiectasis Study(DIBS)
Funder: Department of Health and Social Care

Abstract: Bronchiectasis is a long-term lung condition, unrelated to smoking characterised by chronic sputum (phlegm) production and repeated chest infections. It has significant impacts on quality of life, causes over 4000 hospital admissions per year and shortens lifespans. One in 4 with severe bronchiectasis dies within 4 years. There are over 300,000 patients in the UK with bronchiectasis but international guidelines note the lack of good research studies in the area. No treatments have yet been approved specifically for bronchiectasis._x000D_ _x000D_ Standard care is chest clearance physiotherapy (coughing exercises) and antibiotics for acute infections. Treatments used to prevent infections have very limited evidence; those used include long term antibiotics. Finding treatments that avoid daily antibiotics for lifare attractive to patients. We will study if commonly used inhalers used in to treat smoking related chronic obstructive pulmonary disease (COPD) will work in bronchiectasis. National surveys show up to 80% of patients with bronchiectasis are already treated with inhaled drugs that may open up airways (bronchodilators from two different types; dual long acting bronchodilators) or are inhaled anti-inflammatory drugs (Inhaled steroids (ICS))._x000D_ Bronchodilators might help in bronchiectasis by opening up airways and improving chest clearance whilst ICS might improve airway inflammation. ICS are powerful anti-inflammatories. ICS reduce chest infections in smoking-related COPD but they do increase the rates of pneumonia. The lack of evidence for using ICS in bronchiectasis plus the potential to cause side effects means bronchiectasis guidelines recommending they are not used. Newer dual long acting bronchodilators have recently been shown to be as good as/better than ICS in selected COPD patients. Triple therapy (long acting dual bronchodilators plus inhaled corticosteroids) has a cost of nearly £100 per month; the NHS could be spending over £100M/year on asthma/COPD inhalers in bronchiectasis with no evidence._x000D_ We will undertake a study of 600 patients. All patients will get short acting bronchodilators for symptomatic relief. A computerised program will randomly allocate participants to one of 3 arms _x000D_ 1) newer dual bronchodilators (40%) _x000D_ 2) newer triple therapy (40%) and _x000D_ 3) A smaller group of patients will receive dummy treatment (placebo inhalers; 20%)._x000D_ This will allow us to compare if triple therapy or dual bronchodilator therapy is better than using no long-acting drugs. Participants will receive study medications for a year and neither the patients nor the study team will know if they are on active treatment. _x000D_ We will record how many chest infections occur as our main finding and also how people feel (health- related quality of life) and breathing tests. The study is simple for patients and will only require 4 study visits to the study centres. This will be the world’s first large study of longer acting bronchodilator drugs in bronchiectasis. Our study will allow us to ensure that patients are given the most effective treatment._x000D_ The study team are highly experienced having conducted many prior trials in bronchiectasis and are key members of national guidelines group ensuring both effective study delivery and helping shape future national guidelines. We have expert patient advice experts in managing patients with bronchiectasis and experts in delivering trials and analysing the results and working out cost benefits of drugs tested.

Lay abstract: Research question- does inhaled dual bronchodilator therapy reduce exacerbations in adult patients with bronchiectasis either as a standalone therapy or in combination with inhaled steroids reduce exacerbations in Bronchiectasis?_x000D_ _x000D_ • Background: Bronchiectasis is a chronic airway syndrome characterised by abnormal airways physiology with airflow obstruction, excessive sputum production, persistent airway infection with episodic infective exacerbations and premature mortality. International guidelines and audits both note that although there are no high quality trials of inhaled drugs in bronchiectasis yet these are widely used. Long acting beta agonists and anti muscarinic (LABA/LAMA) either combined with inhaled corticosteroids (ICS) or alone significantly reduce exacerbations in asthma and chronic obstructive pulmonary disease. These are however different pulmonary disorders and the response to inhaled drugs and potential side effects may be very different in bronchiectasis. To date no adequately powered trial has studied the benefits of bronchiectasis. _x000D_ _x000D_ • Aims and objectives _x000D_ We aim to test the benefits of LABA/LAMA therapy alone or as triple therapy (LABA/LAMA/ICS) as compared to placebo in preventing exacerbations of bronchiectasis. _x000D_ _x000D_ • Methods _x000D_ We aim to study the effects of 2 active arms vs placebo in a multicentre study that leverages the national bronchiectasis network BronchUK (www.bronch.ac.uk) which has established multicentre recruitment of over 1000 patients. We will use our recent consensus on the definition of exacerbations and leverage experience in using patient exacerbation diaries to capture the primary outcome._x000D_ _x000D_ • Primary outcome _x000D_ The primary outcome will be exacerbations that require new systemic antibiotics and/or steroids. We have calculated that a sample size of 232 LABA/LAMA vs 232 Triple therapy Vs 126 placebo patients (~600 in total). The power calculation is derived from the pooling of the 2 active arms. We first test superiority of pooled Dual+Triple vs placebo, assuming a ~20% effect size reducing exacerbations (from a mean of 1.9 to 1.5 per year) which has >80% power at a 5% two-sided significance level. If this is significant, we then test non-inferiority of dual vs triple at a NI margin of 0.3 (20% relative NI margin), which has >80% power._x000D_ _x000D_ • Timelines for delivery _x000D_ We have obtained all regulatory approvals in January and February 2021. We initiated recruitment to the internal pilot with the aim to have 10 - 15 centres contributing to the internal pilot recruitment of 98 to 125 participants. We will undertake our stop and guidance criteria at this point. We then expect to have 25 sites recruiting patients at a target of 1-2 particpants per month for each over a 14 month period (reaching last patient first visit by August 2023)._x000D_ _x000D_ • Anticipated impact and dissemination_x000D_ We will define the role of LABA/LAMA and/or triple therapy in bronchiectasis. Currently nearly 50% of patients in the UK national audit of bronchiectasis were on some inhaled therapy with little evidence of efficacy. Our trial will be one of the largest conducted to date in bronchiectasis, leading to definitive guideline recommendations and will change international practice with a major impact in bronchiectasis.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY