Mucoactive drugs for acute respiratory failure: A 2x2 factorial, randomised, controlled, open-label, Phase 3, pragmatic, clinical and cost effectiveness trial with internal pilot

Research question: What is the clinical and cost effectiveness of mucoactive drugs in acute respiratory failure (ARF)? Design:

A 2x2 factorial, randomised, controlled, allocation concealed, open-label, Phase 3, pragmatic, clinical and cost effectiveness trial with internal pilot Setting: 40 general intensive care units (ICUs) throughout the whole UK Target population:

Adult, critically ill patients admitted to the ICU with ARF, defined as any condition resulting in inadequate gas exchange requiring invasive mechanical ventilation Inclusion criteria include: 1. Adult (>=18-years) 2. An acute and potentially reversible cause of ARF as determined by the treating physician

3. Receiving invasive mechanical ventilation 4. Anticipated to remain on invasive mechanical ventilation for at least 48 hours 5. Presence of thick airway secretions Exclusion criteria include: 1. Pre-existing chronic respiratory condition requiring routine use of any mucoactive drug 2. Mucoactive drug treatment started more than 24 hours before trial enrolment

3. Active peptic ulceration (contraindication to carbocisteine) 4. Treatment withdrawal expected within 24 hours 5. Pregnancy 6. Previous enrolment in the trial 7. Declined consent Health technologies being assessed: 1. Topical (nebulised) hypertonic saline (7% or equivalent, four times daily) 2. Systemic carbocisteine (750mg, three times daily)

Measurement of costs and outcomes

Primary: Duration of mechanical ventilation, defined as time from randomisation until first successful unassisted breathing or death

Secondary: In hospital: Extubation; Re-intubation; Duration of ICU and hospital stay; Mortality; Respiratory physiotherapy input; Antibiotic usage; Adverse events At 60 days: Health-related quality of life; Mortality At 6 months: Health-related quality of life; Mortality; Health service use since hospital discharge

Health economic evaluation: We will assess within-trial cost-effectiveness from an NHS and personal social services perspective at 6 months. Sample size: 1956 patients in total. Timeline:

After 6 months’ set-up time including the first 15 sites, recruitment will commence at an average rate of 1.5 patients/ICU/month. Allowing for a staggered start of 6 months to set up the remaining 25 sites, the total duration required for recruitment is 36 months. An internal pilot will be conducted over the first 6 months of recruitment. Allowing 6 months for follow-up and 3 months for final analysis and reporting, the total duration of the project will be 51 months.

Expertise:

Our multiprofessional team includes clinical trialists, national leaders in critical care, clinical experts (physiotherapy, medicine, pharmacy, nursing), methodologists, statistician, health economist, and former patient and family representatives, to optimise all aspects of trial delivery. Anticipated impact and dissemination:

The results of this trial will have significant impact across patient benefit, change in clinical practice, and conduct of future trials. Dissemination will take multiple routes including publication in international, high impact factor, journals, presentation at relevant national and international conferences, and circulation via relevant patient and family networks.