Title: A 2x2 factorial randomised open label trial to determine the clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in bronchiectasis
Funder: Public Health Agency, NI

Abstract: AIMS: We will investigate if nebulised salty water (hypertonic saline) or a tablet called carbocisteine reduce exacerbations, or flare-ups of symptoms, in patients with bronchiectasis compared to usual care that does not include either of these medications as standard. BACKGROUND TO THE RESEARCH: People with bronchiectasis often have excess mucous in their lungs, and breathing exercises are recommended to help clear this. If the mucous builds up it can become a breeding ground for infection, symptoms will get worse, and antibiotics may be required. Treatments like hypertonic saline and carbocisteine might help to thin the mucous and make it easier for patients to cough up. A nebuliser device delivers hypertonic saline in the form of a mist that can be breathed in. Hypertonic saline and carbocisteine reduce the need for antibiotics in other respiratory conditions but we do not yet know if they work in BE. We have done a small study with 19 patients that showed hypertonic saline was safe to use. In the current study we will test if it is helpful for people with BE. To allow us to ‘kill two birds with one stone’, we will also test whether a tablet called carbocisteine is helpful on its own, or in combination with hypertonic saline. DESIGN AND METHODS: We will compare the effect of hypertonic saline and carbocisteine to that of usual care. We will also explore the effect of taking the two medications together. The study will take place in 16 hospitals in the UK that are experienced in the treatment of bronchiectasis. We aim to involve 380 patients with bronchiectasis. With their permission, these participants will be divided randomly into four groups of 95 to provide a fair test of these interventions. The groups will use hypertonic saline, carbocisteine, both hypertonic saline and carbocisteine, or usual care alone. The study will run for 2 years; in the first year, patients will receive their allocated treatment. At the end of year 1, patients will stop receiving treatment as part of the research but will still be followed-up by the research team until the end of year 2. Participants are asked to attend for six visits in total. To keep these visits short, we will record basic information only to determine whether hypertonic saline or carbocisteine are beneficial. This will include information on quality of life, antibiotic use, lung function and symptoms. PATIENT AND PUBLIC INVOLVEMENT: We have discussed our study with bronchiectasis patients and they have contributed to its design. For example, they advised us about the number of tests to do, and recommended that we keep each visit as short as possible. Fiona Copeland, a bronchiectasis carer and Chair of Primary Ciliary Dyskinesia Family Support Group UK, is a grant co-applicant and helped develop the protocol for this study. She continues to advise on trial conduct. In addition, a PPI group reviewed participant information. This study is important for finding the best treatments for patients with bronchiectasis. To help inform clinical practice we will publish our results in medical journals. To ensure that patients and their families/carers are informed of the results directly, we will also present the findings to patient groups and in patient newsletters etc.

Lay abstract: DESIGN: A multicentre 2x2 factorial randomised open label clinical and cost-effectiveness trial in BE with an internal pilot. SETTING: 16 NHS sites part of NIHR LCRN/NICRN, BRONCH-UK and/or EMBARC networks. POPULATION: 380 adults with confirmed diagnosis on HRCT/CT of BE and two or more pulmonary exacerbations within the last year requiring antibiotics. INCLUSION CRITERIA: BE on HRCT/CT; BE the primary respiratory diagnosis; =2 exacerbations in the last year; daily sputum; stable for =14 days; willing to continue existing medication; females must be surgically sterile, postmenopausal or willing to use contraception. EXCLUSION CRITERIA: patients <18 years old; Cystic Fibrosis; COPD as primary diagnosis; current smokers and male ex-smokers with >25 pack years or female ex-smokers with >20 pack years; FEV1<30%; long-term macrolides started within 1 month; regular isotonic saline; treatment with study drugs or other mucoactive within 30 days; intolerance or contraindication to HTS/carbocisteine; hypersensitivity to carbocisteine or its excipients; peptic ulceration; hereditary galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption; patients unable to swallow oral capsules; women pregnant or lactating; participation in a CTIMP within 30 days. HEALTH TECHNOLOGY: Assessment of the clinical and cost-effectiveness of HTS 6% and carbocisteine (alone, or in combination) for airway clearance over 52 weeks in bronchiectasis, with a 52-week follow-up period. Patients randomised to receive either (i) nebulised HTS (6%), (ii) carbocisteine, (iii) a combination of nebulised HTS (6%) and carbocisteine, or (iv) standard care alone. All patients irrespective of group allocation will receive usual care including airway clearance techniques according to BTS guidelines. OUTCOMES: The primary outcome is mean number exacerbations over 52 weeks. Secondary outcomes include disease-specific HRQoL, time to next exacerbation, number of days of antibiotics, generic HRQoL, health service use, QALY, health impairment, treatment satisfaction, adverse events, lung function, and adherence. SAMPLE SIZE: For the primary outcome, based on a pooled SD of 0.9 exacerbations, 216 patients would allow detection of a mean difference between groups of 0.4 exacerbations with 90% power and at the 5% significance level. To allow for potential interaction between interventions, 50% inflation has been included, to 324 patients. Assuming an approximate dropout of 15% gives 380 patients (95 in each group) and over 90% power to detect a minimally important difference of 8 points for the QoL-B scale (SD of 18) at the 5% significance level. This sample size is also sufficient to detect a 75% increase in median time to exacerbation at 98% power, and a medium effect size for other secondary outcomes at 95% power and 5% level of significance. RANDOMISATION: Patients randomised at a 1:1:1:1 ratio using an automated randomisation system. Randomisation stratified by site, to minimise baseline imbalances in antibiotic use in the last year, and current use of macrolides. EXPERTISE: Co-applicants are members of NIHR LCRNs/NICRN and BRONCH-UK and/or EMBARC. All are experts in clinical trial methodology, have led international multicentre trials and have published widely.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY