A trial of common mucoactives used to help airway clearance in patients with respiratory failure requiring mechanical ventilation
| ISRCTN | ISRCTN17683568 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17683568 |
| EudraCT/CTIS number | 2021-003763-94 |
| IRAS number | 293630 |
| Secondary identifying numbers | 20131DMcA-AS, IRAS 293630, HTA - NIHR130454, CPMS 51165 |
- Submission date
- 11/11/2021
- Registration date
- 25/11/2021
- Last edited
- 09/04/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Respiratory
Plain English Summary
Background and study aims
When patients are critically ill, one of the main complications is called acute respiratory failure. This is when a patient’s illness causes their lungs to fail to work (lung failure). Patients need to be admitted to the Intensive Care Unit (ICU) and often need to have a breathing machine, or ventilator, to help them breathe and ensure that enough oxygen gets into their blood.
However, one problem that can occur as a result of being on a ventilator is difficulty clearing secretions (mucus, or sputum) from the lungs. Not being able to clear secretions from the lungs can make breathing harder, and this may result in developing a lung infection (called ventilator-associated pneumonia).
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 secretions.
In some cases, medications called ‘mucoactives’ may be prescribed for patients. Mucoactives are medications that work to help clear secretions from the airways. Two examples of mucoactives are carbocisteine and hypertonic saline. Carbocisteine can help by changing the thickness and stickiness of secretions, which may help clear mucus from the lungs. It is given to patients in the ICU whilst they are on a breathing machine in either liquid form or as a powder dissolved in water, through the patient’s feeding tube. Hypertonic saline is salty water that is delivered into the airways via a device called a nebuliser, which turns the salty water into a mist. The mist may stimulate coughing to help clear thick secretions from the lungs.
Carbocisteine and hypertonic saline are commonly given to patients with long-term respiratory conditions such as bronchiectasis or cystic fibrosis, as they have been shown to be helpful. The researchers carried out a survey of UK ICUs and found that about a third of patients on a breathing machine (ventilator) with lung failure were receiving a mucoactive, and carbocisteine and hypertonic saline were the most commonly used. However, it is not known for certain if these medications work in patients admitted to the ICU with lung failure.
The aim of this study is to investigate whether using one, or both, of these mucoactives (carbocisteine and hypertonic saline) really helps patients when they have difficulty clearing secretions, and if as a result, this means patients spend less time on the breathing machine (ventilator). The researchers will also determine whether these mucoactives can improve other important outcomes for patients during their ICU stay, such as being taken off the breathing machine (ventilator) and having the breathing tube removed (extubation), the need to have the breathing tube put back in (reintubation), and how long patients stayed in the ICU and in hospital. The researchers will record whether patients experience any side effects from the use of these mucoactives.
Who can participate?
Critically ill patients (aged 16 years and over) admitted to the ICU with acute respiratory failure and requiring invasive mechanical ventilation, with secretions that are difficult to clear with usual airway clearance management (as assessed by the treating clinical team).
What does the study involve?
Participants will be put into one of four different groups by chance. The treatments for each group are as follows:
Group 1: Carbocisteine (750 mg, three times daily) plus usual airway clearance management (described below)
Group 2: Hypertonic saline (4 ml, four times daily) plus usual airway clearance management
Group 3: Carbocisteine (750 mg, three times daily) and hypertonic saline (4 ml, four times daily) plus usual airway clearance management
Group 4: Usual airway clearance management (including suctioning, heated humidification, respiratory physiotherapy, with or without isotonic saline), and no mucoactive medication.
If a patient is allocated to receive a mucoactive, they will be given this daily for the duration of their stay in intensive care up to a maximum of 28 days (or up to 29 or 30 days if they start breathing without assistance on Day 27 or Day 28 respectively).
The researchers will ask patients to complete a brief questionnaire about their quality of life at discharge from the ICU and after 2 and 6 months. They will ask patients to fill out a questionnaire at 6 months about their healthcare use to find out if there are any differences between the study treatment groups. They will also take samples of airway secretions and blood from patients to determine the ways in which these mucoactives might work, in order to improve lung failure treatments for patients in the future.
What are the possible benefits and risks of participating?
Taking part in this study may contribute to improved treatment of patients with lung failure in the future. Possible disadvantages of taking part are completing the questionnaires at 2 and 6 months after leaving the hospital. However, these questionnaires are sent to patients in the post or by email to make it more convenient for them to complete. While a patient is in the ICU, they may experience some side effects from receiving one or either of the mucoactives. While in the ICU, the doctors will closely monitor a patient’s response to the medication, including any side effects. If any side effects occur, the doctors will decide whether it is appropriate to continue the medication.
Where is the study run from?
Northern Ireland Clinical Trials Unit (UK)
When is the study starting and how long is it expected to run for?
May 2021 to July 2025
Who is funding the study?
The National Institute for Health Research Health Technology Assessment Programme (NIHR HTA) (UK)
Who is the main contact?
Dr Bronwen Connolly
MARCH@nictu.hscni.net
Contact information
Scientific
School of Medicine, Dentistry and Biomedical Sciences
Queen’s University Belfast
97 Lisburn Road
Belfast
BT9 7BL
United Kingdom
 ORCID ID |
0000-0002-5676-5497 |
|---|---|
| Phone | +44 (0)28 9097 2215 |
| b.connolly@qub.ac.uk |
Public
Northern Ireland Clinical Trials Unit (NICTU)
7 Lennoxvale
Belfast
BT9 5BY
United Kingdom
| Phone | +44 (0)28 961 51447 |
|---|---|
| MARCH@nictu.hscni.net |
Study information
| Study design | 2x2 factorial randomized controlled open-label Phase III pragmatic multi-centre clinical- and cost-effectiveness trial with an internal pilot of two medicinal products (i.e. a Clinical Trial of Investigational Medicinal Products) |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please contact MARCH@nictu.hscni.net to request a participant information sheet. |
| Scientific title | A 2x2 factorial, randomised, controlled, open-label, Phase III, pragmatic, clinical and cost-effectiveness trial with an internal pilot, to determine whether mucoactives (carbocisteine and hypertonic saline) in critically ill patients with acute respiratory failure reduce the duration of mechanical ventilation |
| Study acronym | MARCH |
| Study hypothesis | Patients with acute respiratory failure (ARF) who are treated with mucoactives will have a shorter duration of mechanical ventilation compared to patients receiving usual airway clearance management alone. |
| Ethics approval(s) | Approved 15/10/2021, Yorkshire & The Humber - Leeds East Research Ethics Committee (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, UK; +44 (0)207 104 8105, +44 (0)207 104 8103, +44 (0)207 104 8018; leedseast.rec@hra.nhs.uk), REC ref: 21/YH/0234 |
| Condition | Acute respiratory failure |
| Intervention | Current interventions as of 13/11/2023: Participants will be randomised using an automated web-based or telephone system via randomly permuted blocks in a 1:1:1:1 ratio. There will be stratification by recruitment centre. Intervention 1: Carbocisteine - 750 mg three times daily, for up to 28 days, delivered systemically, plus usual airway clearance management. (Where unassisted breathing commences on Day 27 or Day 28, carbocisteine will be administered up to Day 29 and Day 30 respectively). Intervention 2: Hypertonic saline - 4 ml of 6 or 7% concentration, delivered via nebulisation, four times daily, for up to 28 days, plus usual airway clearance management. (Where unassisted breathing commences on Day 27 or Day 28, hypertonic saline will be administered up to Day 29 and Day 30 respectively). Intervention 3: Carbocisteine and hypertonic saline (as described in 1. and 2.), plus usual airway clearance management. Comparator: Usual airway clearance management including suctioning, heated humidification (either active heated humidification devices, or passive heat and moisture exchangers), and respiratory physiotherapy; use of isotonic saline may also be used depending on clinician preference. _____ Previous interventions: Participants will be randomised using an automated web-based or telephone system via randomly permuted blocks in a 1:1:1:1 ratio. There will be stratification by recruitment centre. Intervention 1: Carbocisteine - 750 mg three times daily, for up to 28 days, delivered systemically, plus usual airway clearance management. (Where extubation occurs on Day 27 or Day 28, carbocisteine will be administered up to Day 29 and Day 30 respectively). Intervention 2: Hypertonic saline - 4 ml of 6 or 7% concentration, delivered via nebulisation, four times daily, for up to 28 days, plus usual airway clearance management. (Where extubation occurs on Day 27 or Day 28, hypertonic saline will be administered up to Day 29 and Day 30 respectively). Intervention 3: Carbocisteine and hypertonic saline (as described in 1. and 2.), plus usual airway clearance management. Comparator: Usual airway clearance management including suctioning, heated humidification (either active heated humidification devices, or passive heat and moisture exchangers), and respiratory physiotherapy; use of isotonic saline may also be used depending on clinician preference. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Carbocisteine, hypertonic saline |
| Primary outcome measure | Duration of mechanical ventilation (in hours), defined (measured) as time from randomisation until first successful unassisted breathing (defined as maintaining unassisted breathing at 48 hours) or death (data obtained from medical notes). This outcome is one of the ‘COVenT’ core outcomes for trials of interventions intended to modify the duration of mechanical ventilation. To clarify: 1. Unassisted breathing is defined as no inspiratory support or extracorporeal lung support 2. Success is defined as maintaining unassisted breathing at 48 hours 3. Duration includes time receiving extracorporeal lung support, invasive mechanical ventilation and non-invasive ventilation delivering volume or pressure support ventilation 4. Duration excludes time receiving high-flow oxygen therapy and continuous positive airway pressure 5. Patients with a tracheostomy in situ may still achieve successful unassisted breathing 6. Follow-up is to 60 days from randomisation |
| Secondary outcome measures | Timepoint: In hospital 1. Extubation - Time (in hours) from randomisation to first successful extubation (success defined as remaining free from endotracheal or tracheostomy tubes at 48 hours); Censored at 60 days; Data obtained from medical notes 2. Re-intubation - Event of reintubation of endotracheal tube after a planned extubation (censored at hospital discharge); excludes temporary reinsertion of endotracheal tube for procedures only; Censored at 60 days; Data obtained from medical notes 3. Respiratory physiotherapy input - Occurrence and frequency of airway clearance sessions; Censored at ICU discharge, death, or Day 28 whichever occurs first (where extubation occurs on Day 27 or Day 28, respiratory physiotherapy input will be recorded up to Day 29 and Day 30 respectively); Data obtained from medical notes 4. Antibiotic usage – Overall dose of individual agents; Censored at ICU discharge, death, or Day 28 whichever occurs first (where extubation occurs on Day 27 or Day 28, antibiotic usage will be recorded up to Day 29 and Day 30 respectively); Data obtained from medical notes 5. Duration of ICU and hospital stay - Time (in days and hours) from randomisation until the patient first leaves the relevant facility or dies; Censored at 6 months; Data obtained from medical notes 6. All-cause mortality - Confirmation and cause of death; Data obtained from medical notes 7. Safety - Censored at ICU discharge, death, or Day 28 whichever occurs first (where extubation occurs on Day 27 or Day 28, safety outcomes will be recorded up to Day 29 and Day 30 respectively); Data obtained from medical notes; to include the following outcomes: 7.1. Clinically important upper gastrointestinal (GI) bleeding due to peptic ulceration confirmed on upper GI endoscopy 7.2. Bronchoconstriction requiring nebulised bronchodilators 7.3. Ventilator or circuit dysfunction with respiratory deterioration 7.4. Hypoxaemia during nebulisation 7.5. Hospital resource use - Number of days at Level of Care 0/1/2/3; Censored at 6 months; Obtained via data linkage with ICNARC (Intensive Care National Audit & Research Centre) and SICSAG (Scottish Intensive Care Society Audit Group) Timepoint: Time of consent to continue Health-related quality of life measured using calculation of quality-adjusted life years (QALYs) via the EQ-5D-5L questionnaire Timepoint: 60 days 1. Health-related quality of life measured using calculation of quality-adjusted life years (QALYs) via the EQ-5D-5L questionnaire 2. All-cause mortality - Confirmation and cause of death; Data obtained from medical notes Timepoint: 6 months 1. Health-related quality of life measured using calculation of quality-adjusted life years (QALYs) via the EQ-5D-5L questionnaire 2. All-cause mortality - Confirmation and cause of death; Data obtained from medical notes 3. Health service use since hospital discharge measured via a study-specific Health Service Use questionnaire which will collect information on the following categories: 3.1. Hospital care: Number of inpatient or day-case hospital admissions; length of stay; the number of hospital outpatient appointments 3.2. Emergency care: Number of visits to Emergency Departments; the number of admissions to hospital after a visit to the Emergency Department 3.3. Care at a GP surgery, health clinic, or other community setting: the number of appointments; type of professional seen 3.4. Health care at home: the number of health care professional visits at home; type of health care professional seen at home 3.5. Medication: Name/class of medication. Oxygen use will also be recorded The secondary outcomes of extubation, re-intubation, duration of ICU and hospital stay, all-cause mortality, and health-related quality of life represent the remaining outcomes in the COVenT core outcome set. |
| Overall study start date | 01/05/2021 |
| Overall study end date | 31/07/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | 1956 |
| Participant inclusion criteria | 1. Aged ≥16 years 2. An acute and potentially reversible cause of ARF as determined by the treating physician 3. Receiving invasive mechanical ventilation via endotracheal tube or tracheostomy 4. Anticipated to remain on invasive mechanical ventilation for at least 48 hours 5. Presence of secretions that are difficult to clear with usual airway clearance management (as assessed by the treating clinical team) |
| Participant exclusion criteria | Current exclusion criteria as of 13/11/2023: 1. Pre-existing chronic respiratory condition receiving routine use of any mucoactive 2. Mucoactive treatment started more than 24 hours prior to trial enrolment 3. Known adverse reaction to either study mucoactive 4. Treatment withdrawal expected within 24 hours 5. Known pregnancy 6. Previous enrolment in the MARCH trial 7. Declined consent 8. The treating physician believes that participation in the trial would not be in the best interests of the patient _____ Previous exclusion criteria: 1. Pre-existing chronic respiratory condition receiving routine use of any mucoactive 2. Mucoactive treatment started more than 24 hours prior to trial enrolment 3. Known adverse reaction to either study mucoactive 4. Treatment withdrawal expected within 24 hours 5. Known pregnancy 6. Previous enrolment in the MARCH trial 7. Declined consent 8. Prisoners 9. The treating physician believes that participation in the trial would not be in the best interests of the patient |
| Recruitment start date | 17/02/2022 |
| Recruitment end date | 30/04/2025 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Liverpool
L7 8XP
United Kingdom
Londonderry
BT47 6SB
United Kingdom
Antrim
BT41 2RL
United Kingdom
Barnsley
S75 2EP
United Kingdom
Birmingham
B15 2GW
United Kingdom
Bristol
BS2 8HW
United Kingdom
Old Dalkeith Road
Edinburgh
Lothian
EH16 4SA
United Kingdom
Newcastle upon Tyne
NE7 7DN
United Kingdom
Newcastle upon Tyne
TS1 4LP
United Kingdom
Glasgow
G4 0SF
United Kingdom
Gloucester
GL1 3NN
United Kingdom
London
SE1 9RT
United Kingdom
London
SE1 7EH
United Kingdom
Hull
HU3 2JZ
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
London
SE5 9RS
United Kingdom
Leicester
LE1 5WW
United Kingdom
Gillingham
ME7 5NY
United Kingdom
Morriston
Swansea
SA6 6NL
United Kingdom
Taunton
TA1 5DA
United Kingdom
Nottingham
NG7 2UH
United Kingdom
Wakefield
WF1 4DG
United Kingdom
Poole
BH15 2JB
United Kingdom
London
SE13 6LH
United Kingdom
London
SE13 6LH
United Kingdom
Rotherham
S60 2UD
United Kingdom
Reading
RG1 5AN
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Truro
TR1 3LJ
United Kingdom
Liverpool
L9 7AL
United Kingdom
Oldham
OL1 2JH
United Kingdom
Stoke-on-Trent
ST4 6QG
United Kingdom
Bath
BA1 3NG
United Kingdom
Belfast
BT12 6BA
United Kingdom
Manchester
M6 8HD
United Kingdom
Birmingham
B18 7QH
United Kingdom
Bristol
BS10 5NB
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Watford
WD18 0HB
United Kingdom
Manchester
M13 9WL
United Kingdom
York
YO31 8HE
United Kingdom
Winchester
SO22 5DG
United Kingdom
Ipswich
IP4 5PD
United Kingdom
Preston
PR2 9HT
United Kingdom
Clydebank
G81 4DY
United Kingdom
Coventry
CV2 2DX
United Kingdom
Cwmbran
NP44 8YN
United Kingdom
Portsmouth
PO6 3LY
United Kingdom
Manchester
M23 9LT
United Kingdom
Manchester
M8 5RB
United Kingdom
Belfast
BT9 7AB
United Kingdom
West Bromwich
B71 4HJ
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Bordesley Green
Birmingham
B9 5ST
United Kingdom
Calow
Chesterfield
S44 5BL
United Kingdom
Headington
Oxford
OX3 9DU
United Kingdom
Kirkcaldy
KY2 5AH
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
Lincoln
LN2 5QY
United Kingdom
Glasgow
G51 4TF
United Kingdom
Plymouth
PL6 8DH
United Kingdom
Willesborough
Ashford
TN24 0LZ
United Kingdom
Yeovil
BA21 4AT
United Kingdom
Airdrie
ML6 0JS
United Kingdom
Bury St. Edmunds
IP33 2QZ
United Kingdom
C Floor, Huntsmnan Building
Herries Road
Sheffield
S5 7AU
United Kingdom
Sheffield
S10 2JF
United Kingdom
Wrexham Technology Park
Wrexham
LL13 7TD
United Kingdom
Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Bedford
MK42 9DJ
United Kingdom
London
NW1 2PG
United Kingdom
Torquay
TQ2 7AA
United Kingdom
Pond Street
London
NW3 2QG
United Kingdom
Warrington
WA5 1QG
United Kingdom
Barnstaple
EX31 4JB
United Kingdom
Sponsor information
Hospital/treatment centre
Research Office
2nd Floor King Edward Building
Royal Victoria Hospital
Grosvenor Road
Belfast
BT12 6BA
Northern Ireland
United Kingdom
| Phone | +44 (0)28 961 56057 |
|---|---|
| Alison.Murphy@belfasttrust.hscni.net | |
| Website | http://www.belfasttrust.hscni.net/ |
"ROR" |
https://ror.org/02tdmfk69 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/11/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The researchers will publish the trial protocol and statistical analysis plan to ensure transparency in their methodology. The study findings will be presented at national and international meetings with abstracts online. Presentation at these meetings will ensure that results and any implications are rapidly disseminated to the wider UK intensive care community. In accordance with the open-access policies proposed by the NIHR the researchers plan to publish the clinical findings of the trial as well as a separate paper describing the cost-effectiveness in the NHS setting in high quality peer-reviewed open access (e.g. including via PubMed Central) journals. A final report will also be published in the NIHR HTA journal. Due to limited resources, it will not be possible to provide each patient with a personal copy of the results of the trial. However, upon request, patients involved in the trial will be provided with a lay summary of the principal study findings. The most significant results will be communicated to the wider public through media releases. An ongoing update of the trial will also be provided on the CTU website. Following the publication of the primary and secondary outcomes there may be scope to conduct additional analyses on the data collected. In such instances formal requests for data will need to be made in writing to the Chief Investigator or Co-Chief Investigator via the Clinical Trials Unit, who will discuss this with the Sponsor. The study will comply with the good practice principles for sharing individual participant data from publicly funded clinical trials and data sharing will be undertaken in accordance with the required regulatory requirements. In the event of publications arising from such analyses, those responsible will need to provide the Chief Investigator or Co-Chief Investigator with a copy of any intended manuscript for approval prior to submission. |
| IPD sharing plan | The datasets generated and/or analysed during the current study will be available upon request following the publication of the primary and secondary outcomes. Formal requests for data should be made in writing to Prof. Danny McAuley (Chief Investigator) or Dr Bronwen Connolly (Co-Chief Investigator) via the Trial Manager, Caroline Wilson (MARCH@nictu.hscni.net). Requests will be reviewed on a case by case basis in collaboration with the Sponsor. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
09/04/2025: The recruitment end date was changed from 28/02/2025 to 30/04/2025.
25/11/2024: Birmingham City Hospital was removed and Northern Devon District Hospital was added to the study participating centres.
15/11/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/10/2024 to 28/02/2025.
2. The intention to publish date was changed from 31/07/2026 to 30/11/2026.
01/08/2024: The target number of participants was changed from 1965 to 1956.
13/11/2023: The following changes were made to the trial record:
1. The public contact was changed.
2. The study participating centres The Royal Marsden Hospital, East Surrey Hospital, Nottingham City Hospital, Peterborough City Hospital, Stoke Mandeville Hospital, Royal Papworth Hospital, Royal Surrey County Hospital were removed and Royal Devon and Exeter Hospital, Lincoln County Hospital, Queen Elizabeth University Hospital, Derriford Hospital, William Harvey Hospital, Yeovil District Hospital, University Hospital Monklands, West Suffolk Hospital, Northern General Hospital, Royal Hallamshire Hospital, Wrexham Maelor Hospital, Glan Clwyd Hospital, Aberdeen Royal Infirmary, Bedford Hospital, University College Hospital, Torbay Hospital, Royal Free Hospital, Warrington Hospital were added.
3. The interventions were changed.
4. The exclusion criteria were changed.
5. The plain English summary was updated to reflect these changes.
01/04/2022: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/02/2022 to 17/02/2022.
2. The trial participating centres Addenbrookes Hospital, Heartlands Hospital, Chesterfield Royal Hospital, John Radcliffe Hospital, Victoria Hospital were added.
07/12/2021: Internal review.
11/11/2021: Trial's existence confirmed by the NIHR.
