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. 2026 Feb 4:1-77.
doi: 10.3310/GGCC1111. Online ahead of print.

A pragmatic, multicentre, placebo-controlled, 3-arm, double-blinded, randomised controlled trial, incorporating an internal pilot, to determine the role of bronchodilators in preventing exacerbations of bronchiectasis

Nina Wilson  1 , Miranda Morton  2 , Tara Homer  3 , Ann Breeze Konkoth  1 , Richard Joyce  2 , Anneka Kershaw  2 , Hazel Wilde  2 , Alison Liddle  2 , James Wason  1 , Laura Ternent  3 , Maria Allen  4 , Robert Lord  5 , John Steer  6 , Graham Devereux  7 , James D Chalmers  8 , Adam T Hill  9 , Charles S Haworth  10   11 , John R Hurst  12 , And Anthony De Soyza  4   13
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Free article

A pragmatic, multicentre, placebo-controlled, 3-arm, double-blinded, randomised controlled trial, incorporating an internal pilot, to determine the role of bronchodilators in preventing exacerbations of bronchiectasis

Nina Wilson et al. Health Technol Assess. .
Free article

Abstract

Background: Bronchiectasis is a long-term lung condition associated with bronchial dilatation, chronic inflammation and infection. Treatment is often empirical or extrapolated from other lung conditions, for example the use of inhaled therapies licensed for use in asthma or chronic obstructive pulmonary disease. Inhaled therapies, such as corticosteroids or long-acting bronchodilators (long-acting beta agonists or long-acting muscarinic antagonists), are commonly used in bronchiectasis despite scanty evidence on exacerbation reduction.

Objective: To assess whether: dual bronchodilators (long-acting beta agonists/long-acting muscarinic antagonists) either as stand-alone therapy or in combination with inhaled corticosteroid are superior to placebo at reducing mean exacerbation rates over 12 months dual bronchodilators (long-acting beta agonists/long-acting muscarinic antagonists) are non-inferior to triple therapy (inhaled corticosteroid/long-acting beta agonists/long-acting muscarinic antagonists) at reducing mean exacerbation rates over 12 months.

Design: Pragmatic, multicentre, placebo-controlled, three-arm, double-blinded, prospective, randomised controlled trial incorporating a 12-month internal pilot.

Target population: Six hundred adults with bronchiectasis and history of ≥ 2 exacerbations in any 12-month period within the preceding 2 years.

Setting: United Kingdom National Health Service secondary care sites.

Interventions: Twelve months, one puff daily of either dual therapy [55 μg umeclidinium (long-acting muscarinic antagonists) and 22 μg vilanterol (long-acting beta agonists)], triple therapy [dual therapy plus 92 μg fluticasone furoate (inhaled corticosteroid)] or matched placebo dry powder inhalers, randomised in a 2 : 2 : 1 ratio, respectively.

Outcome measures: Primary: number of participants reported bronchiectasis exacerbations requiring treatment with antibiotics during the 12-month treatment period. Primary economic: incremental cost per quality-adjusted life-year gained at 12 months.

Results: Recruitment rates did not follow projections due to the COVID-19 pandemic; 85 potentially eligible patients were screened, of whom 33 (39%) were randomised. Of the randomised participants, 30 (91%) completed follow-up at 12 months; 3 participants withdrew [1/14 (7%) dual therapy, 1/12 (8%) triple therapy and 1/7 (14%) placebo]. Five participants discontinued therapy during the trial [1/14 (7%) dual therapy, 2/12 (17%) triple therapy and 2/7 (29%) placebo]. Given the small sample size, the statistical and economic analyses are descriptive and exploratory. Exacerbation data were available for 32/33 (97%) of randomised participants (13 dual therapy, 12 triple therapy and 7 placebo). The median number of exacerbations during the follow-up (the primary outcome) was 1 (interquartile range 0-3) for dual therapy, 2 (1, 2.5) for triple therapy and 3 (2, 3) for placebo. No safety concerns were identified. Complete resource-use and quality-of-life data were available for 30/33 (91%) participants.

Conclusions: COVID-19 impacted delivery of the trial, affecting staff capacity, setting up of timelines, and ultimately, recruitment to the pilot. There was good retention and data completeness within the trial randomised participants. The trial is unable to provide evidence on the superiority or cost-effectiveness of dual or triple therapy to placebo at reducing mean exacerbation rates over 12 months or the non-inferiority of dual to triple therapy.

Future work and limitations: The main limitation of this work is the small sample size that prevents any firm conclusions to be made. However, the results do suggest that there is a signal of efficacy and that a larger trial is needed to provide valuable clinical evidence. These results underscore the importance of completing a large-scale trial of these therapies to help improve the understanding and best treatment for patients with bronchiectasis.

Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR127460.

Keywords: ADULT; BRONCHIECTASIS; BRONCHODILATOR AGENTS; FLUTICASONE FUROATE; HUMANS; INHALED CORTICOSTEROID; MUSCARINIC ANTAGONISTS; PROSPECTIVE STUDIES.

Plain language summary

Bronchiectasis is a long-term lung condition. People with it cough more, make more mucus, have shortness of breath and repeated chest infections (flare-ups). Reducing the number of flare-ups is key for patients, but there is no inhaled medication approved specifically to treat bronchiectasis. Instead, treatments given are ones used to treat other lung conditions. This trial aimed to see if two different types of inhalers, dual therapy and triple therapy, reduce flare-ups. Dual therapy contains two medicines that help to open up airways and make breathing easier. Triple therapy contains these same two medicines and a medicine to reduce inflammation. These inhalers were compared to a ‘dummy’ or placebo inhaler that contains no medicine. Which inhaler participants took was decided by a computer at random. All inhalers were identical, and participants and their doctors did not know which one they were taking. One puff of the inhaler was taken once a day for 12 months. Patients were recruited from nine United Kingdom National Health Service hospitals, but not at the rate expected. When 33 participants were recruited instead of the 120 expected at that time point, the trial was closed early because of slow recruitment. The COVID-19 pandemic had a big impact. It meant that hospitals had longer timelines due to setting up the trial and less staff available. Patients were shielding and worried about visiting hospitals. Results show that 14 participants took dual therapy, 12 took triple therapy and 7 took placebo. On average, participants taking dual or triple therapy had less flare-ups and had more time to having their first flare-up than those taking placebo. Though we cannot make firm conclusions because of the small number of participants, the results highlight the importance of completing a large-scale trial of these therapies to help improve understanding of the best treatment for bronchiectasis.

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References

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