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

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 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.