# Effectiveness of mucoactives (carbocisteine and hypertonic saline) in addition to usual airway clearance management with usual airway clearance management alone in acute respiratory failure (MARCH): study protocol for a multi-centre 2x2 factorial, randomised, controlled, open-label, Phase 3, pragmatic, clinical and cost-effectiveness trial with internal pilot

## TL;DR

This study will test if adding carbocisteine or hypertonic saline to standard care improves outcomes for ICU patients with breathing difficulties.

## Contribution

The study introduces a large-scale trial to evaluate the clinical and cost-effectiveness of mucoactives in acute respiratory failure.

## Key findings

- The trial will compare four treatment groups to assess the impact of mucoactives on ventilation duration.
- It will evaluate safety, clinical outcomes, and cost-effectiveness in ICU patients.
- Results will inform clinical guidelines and patient care practices.

## Abstract

Usual airway clearance management in critically ill patients with acute respiratory failure includes suctioning, humidification, use of isotonic saline, and respiratory physiotherapy techniques. Escalation to use of mucoactives occurs when secretions are difficult to clear. Use of mucoactives in clinical practice for this patient population is extensive, yet empirical and variable. Carbocisteine and hypertonic saline are the most used agents, but evidence for their effectiveness is absent or minimal. The lack of existing large-scale randomised trials comparing mucoactives to usual airway clearance management alone in critically ill patients with acute respiratory failure highlights the urgency and necessity of this study.

To determine whether the use of mucoactives in critically ill patients with acute respiratory failure improves clinical outcomes and is cost effective, compared to usual airway clearance management alone.

A UK multi-centre, 2x2 factorial, randomised, controlled, open-label, Phase 3, pragmatic, clinical and cost effectiveness trial with internal pilot. The target sample is 1956 critically ill adults. Participants will be equally allocated across four trial arms. All participants will receive usual airway clearance management. In three intervention groups, participants will receive either carbocisteine, hypertonic saline, or a combination of carbocisteine and hypertonic saline. In the fourth comparator group, participants will receive usual airway clearance management alone. The primary outcome is the duration of mechanical ventilation with secondary clinical, safety, and health resource utilisation outcomes. The trial will be reported in accordance with CONSORT guidelines. Ethical approval was granted by Leeds East (Yorkshire & The Humber) Research Ethics Committee (reference 21/YH/0234) on 28
th October 2021. All participants will provide written, informed consent via either Personal or Professional Legal Representatives, and subsequently directly once capacity is regained.

Main trial: ISRCTN17683568,
https://www.isrctn.com/ISRCTN17683568, 25
th November 2021

Study Within A Trial: ISRCTN16675252,
https://www.isrctn.com/ISRCTN16675252, 3
rd November 2021

EudraCT Number, 2021-003763-94

Many patients admitted to an intensive care unit (ICU) need help to breathe from a breathing machine (ventilator). However, one problem that can occur because of being on a ventilator, is difficulty clearing secretions from the lungs. These secretions can make breathing harder if they become very thick and dry. 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. We found that about one-third of patients on a ventilator in UK ICUs receive a mucoactive drug. Two common examples are 'hypertonic saline' and 'carbocisteine'. However, we do not know if these drugs really help patients with thick secretions or not.

In our trial we want to know if using one, or both, of these drugs helps with clearing thick secretions, and if as a result, this means patients spend less time on the ventilator. Patients will be allocated to one of four groups in the trial by chance. We will compare how much time patients spend on the ventilator between each group. We also want to know how safe the drugs are, and if they can improve other important outcomes during the ICU stay. Additionally, we will also look at value for money.

At the end of the trial, we will share our findings with ICUs, clinicians, researchers, and patient groups to help improve patient care. Our team includes physiotherapists, doctors, nurses, pharmacists, health economists, statisticians, former patients and family members, and others who have expertise in this type of research. Together they will ensure the trial is delivered successfully.