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

Abstract: Many patients in intensive care (ICU) need help to breathe from a breathing machine (ventilator). However, one problem that can occur as a result of being on a ventilator, is difficulty clearing secretions (mucus) from the lungs. These secretions can make breathing harder if they become very thick and dry. The breathing tube from the ventilator can make coughing up secretions more difficult. Patients may also feel too sleepy from their medication to cough by themselves. This may result in developing a lung infection (called ventilator-associated pneumonia). _x000D_ _x000D_ To reduce the problem of thick secretions, the air coming from the ventilator can have moisture added to it (humidification). Other treatments can include using a suction tube to remove secretions via the breathing tube. Physiotherapists may also use techniques to help clear thick secretions. In some cases medications called mucoactive drugs may be prescribed. Two common mucoactive drugs used in ICUs in the UK are ‘hypertonic saline’ and ‘carbocisteine’. We conducted a survey of UK ICUs and found that about one-third of patients on a ventilator will be receiving a mucoactive drug. However, we do not know if these mucoactive drugs really help patients with thick secretions or not._x000D_ _x000D_ In our trial we want to know if using one, or both, of these mucoactive drugs helps with clearing thick secretions, and if as a result, this means patients spend less time on the ventilator. We also want to know how safe they are, and if they can improve other important outcomes during the ICU stay. _x000D_ _x000D_ Our trial will include 1956 patients from 40 ICUs across the UK, who need to be on a ventilator for at least 2 days, and who have thick secretions. Patients will be allocated to one of four groups by chance. Group 1 will receive usual care (all of the normal treatments for clearing thick secretions, but no mucoactive drug); Group 2 will receive usual care plus hypertonic saline; Group 3 will receive usual care plus carbocisteine; Group 4 will receive usual care plus both hypertonic saline and carbocisteine. We will compare how much time patients spend on the ventilator between each group. We will find out if there was a difference between each group in patients being taken off the ventilator (extubated), needing to have the breathing tube put back in (reintubation), and how long they stayed in the ICU. Patients will be followed up for 6 months afterwards to compare if there were differences in the after-effects of being ill in ICU between the groups. We will record how long patients spent in hospital, and ask them to complete a brief questionnaire to tell us how they feel about their quality of life. We will record whether any patients died. Additionally, we will also be looking at value for money. Mucoactive drugs such as hypertonic saline and carbocisteine are generally not very expensive. However, if they are prescribed unnecessarily and in many patients, this could be very costly overall for the NHS. At the end of the trial, we will share our findings with other ICUs, clinicians, researchers, and patient groups to help improve patient care._x000D_ _x000D_ We have a large experienced team of people guiding this study. They include physiotherapists, doctors, nurses, pharmacists, health economists, statisticians, former patients and family members, and others who have expertise in the study methods. Together they will ensure the trial runs smoothly, safely, and finishes on time.

Lay abstract: Research question: _x000D_ What is the clinical and cost effectiveness of mucoactive drugs in acute respiratory failure (ARF)?_x000D_ _x000D_ Design: _x000D_ A 2x2 factorial, randomised, controlled, allocation concealed, open-label, Phase 3, pragmatic, clinical and cost effectiveness trial with internal pilot_x000D_ _x000D_ Setting: _x000D_ 40 general intensive care units (ICUs) throughout the whole UK_x000D_ _x000D_ Target population: _x000D_ Adult, critically ill patients admitted to the ICU with ARF, defined as any condition resulting in inadequate gas exchange requiring invasive mechanical ventilation_x000D_ _x000D_ Inclusion criteria include:_x000D_ 1. Adult (>=18 years)_x000D_ 2. An acute and potentially reversible cause of ARF as determined by the treating physician_x000D_ 3. Receiving invasive mechanical ventilation_x000D_ 4. Anticipated to remain on invasive mechanical ventilation for at least 48 hours_x000D_ 5. Presence of thick airway secretions_x000D_ _x000D_ Exclusion criteria include:_x000D_ 1. Pre-existing chronic respiratory condition requiring routine use of any mucoactive drug_x000D_ 2. Mucoactive drug treatment started more than 24 hours before trial enrolment_x000D_ 3. Active peptic ulceration (contraindication to carbocisteine)_x000D_ 4. Treatment withdrawal expected within 24 hours_x000D_ 5. Pregnancy_x000D_ 6. Previous enrolment in the trial_x000D_ 7. Declined consent_x000D_ _x000D_ Health technologies being assessed: _x000D_ 1. Topical (nebulised) hypertonic saline (7% or equivalent, four times daily)_x000D_ 2. Systemic carbocisteine (750mg, three times daily)_x000D_ _x000D_ Measurement of costs and outcomes_x000D_ Primary: Duration of mechanical ventilation, defined as time from randomisation until first successful unassisted breathing or death_x000D_ Secondary: In hospital: Extubation; Re-intubation; Duration of ICU and hospital stay; Mortality; Respiratory physiotherapy input; Antibiotic _x000D_ usage; Adverse events_x000D_ At 60 days: Health-related quality of life; Mortality_x000D_ At 6 months: Health-related quality of life; Mortality; Health service use since hospital discharge_x000D_ Health economic evaluation: We will assess within-trial cost-effectiveness from an NHS and personal social services perspective at 6 months._x000D_ _x000D_ Sample size: _x000D_ 1956 patients in total._x000D_ _x000D_ Timeline: _x000D_ 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._x000D_ _x000D_ Expertise: _x000D_ 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. _x000D_ Anticipated impact and dissemination: _x000D_ _x000D_ 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.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY