Title: A 2x2 factorial randomised single blind open labelled trial to determine the clinical and cost-effectiveness of hypertonic saline ((HTS 6%) and carbocysteine versus usual care over 12 months in non-cystic fibrosis bronchiectasis (BE):
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Design: A 12m multicentre, 2x2 factorial randomised single blind open labelled trial in BE with a 12m follow-up period. Internal Pilot Study: Months 4-9 and will confirm recruitment rates, protocol compliance and data collection. Setting: 16 NHS sites part of the Bronch-UK/NIHR-NICRN. Population: 380 adult patients with BE. Inclusion:BE on HRCT; 2 or more exacerbations in the last year; daily sputum, stable for at least 14 days; willing to continue existing medication during the study. Exclusion: CF; FEV1<30%;inhaled antibiotic/investigational drug within 28d; on long term macrolides started within 3m. of commencing study. Health Technology: Intervention 1: Standard care and twice daily nebulised HTS(7%) over 12 months: Intervention 2: Standard care and carbocysteine: Intervention 3: Combination of twice daily nebulised HTS (7%)and carbocysteine over 12 months. Intervention 4: standard care over 12 months. All groups will have a 12m follow-up. Outcome: Patients will be followed up at 5 time points Year 1 and 1 time points in Year 2. Outcomes: Primary: HRQoL at 12m. Secondary: time to next exacerbation; lung function, mean number exacerbations, total number of days of antibiotics;resource use and QALY over the 24m. Adverse events, satisfaction. Sample size: Based on a SD for QOL-B of 18 for the usual care group (16) and a MID of 8 points (16), 214 patients would be required at 90% power and p=0.05. To allow for a potential interaction between the two interventions, a 50% inflation has been included, to 321 patients. Assuming 15% dropout gives a total of 378 patients (95 in each of the four groups). This sample size would be sufficient to detect a 75% increase in median time to exacerbation at 98% power; a medium effect size for other secondary outcomes at 95% power and p=0.05. Randomisation: Secure interactive voice response randomisation service in a 1:1:1:1 ratio. Stratified randomisation to minimise baseline imbalances in antibiotic use in the last year. Difference in pathways: The planned care pathway will be the same as current care except that patients will receive nebulised HTS/carbocysteine/combination and attend for study visits. Statistical Analysis: Intention-to-treat, with significance as a two-tailed p-value of <0.05. Groups will be compared for the primary outcome (QOL-B) and other continuous outcomes using analysis of variance (ANOVA). The factorial design permits the separate testing of the effects of HTS and carbocysteine on HRQoL and the detection of any interaction between them. These tests will be implemented using three contrasts (representing HTS, carbocysteine, and the interaction) in the ANOVA model. Analysis of covariance (ANCOVA) will be used to adjust for baseline characteristics and other covariates. For time to next exacerbation, Kaplan-Meier survival analysis and the log-rank test to compare the groups. The economic evaluation is described in “Change section” Timetable with milestones (M): start: October 2017; study set-up, (m3). M1: MHRA/regulatory approval (m1-3). Recruitment 12 patients per site per month over a 12 month recruitment period (m4-16) and trial execution (m4-36). M2: Achievement recruitment feasibility milestones in internal pilot study (m 9): Data analysis and manuscript preparation (m42-48). Expertise: The team are members of Bronch-UK, UK/NICRN and experts in clinical trial methodology. All applicants have lead international multicentre trials and have published widely.

Lay abstract: Aims: We will test if nebulised salty water (hypertonic saline) or a medication called carbocysteine (a tablet that makes mucous less sticky) improves quality of life and reduces exacerbations (flare ups), compared to usual care (that does not usually include either the nebulised salty water or the tablet that makes mucous less sticky) for patients with BE. Background to the research: People with BE often have more mucous to clear from their lungs. In order to stay well they have to do breathing exercises to help clear this mucous. If the mucous builds up, it can become a breeding ground for infection, the patient’s symptoms will get worse, and they might need to take antibiotics. Treatments like hypertonic saline and carbocysteine might help to thin the mucous and make it easier for patients to cough up mucous. Hypertonic saline is used with a nebuliser and it forms a mist that can be breathed in. Hypertonic saline and carbocysteine reduce the need for antibiotics in other respiratory conditions but we do not know if they work in BE. We have done a small study with 19 patients which showed that hypertonic saline was safe to use. In this bigger study we will show 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 carbocysteine is also helpful. Design and methods used: We will compare the effect of hypertonic saline and the effect of carbocysteine to usual care. We will also be able to explore the effect of taking the two medications together. The study will take place in 16 hospitals in the UK that know how to treat people with BE. We will include 380 patients with BE, who, with their permission, will be divided randomly into four groups of 95 patients to provide a fair test of these interventions. The groups will use hypertonic saline, carbocysteine, both hypertonic saline and carbocysteine or just usual care. 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 the study but may/may not remain on the treatment and will still be followed up by the research team. They will be asked to attend for 6 visits in total. To keep the visits short. we will record basic information only to determine whether hypertonic saline or carbocysteine are beneficial. This will include information on quality of life, antibiotic use, lung function and symptoms. These assessments will be carried out by research coordinators who are not aware of treatment the patient has received. This is important to ensure that researchers cannot influence the results in any way. Patient and public involvement: We have discussed our study with people with BE and they have helped us to prepare the study. They advised us about the number of tests to do, and to keep each visit short. In addition, Fiona Copeland, who cares for two BE patients and chairs the PCD Family Support Group UK will help us by advising on patient leaflets. The study is important for finding the best treatments for patients with BE. To help inform clinical practice we will publish the results of this high quality study in medical journals. We will also publish the findings in patient newsletters, and present them to patients and their families/carers so that they hear the results directly.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY