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
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	2021-003763-94
Integrated Research Application System (IRAS)	293630
Protocol serial number	20131DMcA-AS, IRAS 293630, HTA - NIHR130454, CPMS 51165
Sponsor	Belfast Health and Social Care Trust
Funder	Health Technology Assessment Programme

Submission date: 11/11/2021
Registration date: 25/11/2021
Last edited: 02/07/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Respiratory

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

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 October 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

Dr Bronwen Connolly
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
Email	b.connolly@qub.ac.uk

Dr Naomi Dickson
Public

Northern Ireland Clinical Trials Unit (NICTU)
7 Lennoxvale
Belfast
BT9 5BY
United Kingdom

Phone	+44 (0)28 961 51447
Email	MARCH@nictu.hscni.net

Study information

Primary study design	Interventional
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)
Secondary study design	Randomised controlled trial
Study type	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 objectives	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
Health condition(s) or problem(s) studied	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
Phase	Phase III
Drug / device / biological / vaccine name(s)	Carbocisteine, hypertonic saline
Primary outcome measure(s)	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
Key secondary outcome measure(s)	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.
Completion date	31/10/2025

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	16 Years
Sex	All
Target sample size at registration	1956
Total final enrolment	1956
Key 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)
Key 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
Date of first enrolment	17/02/2022
Date of final enrolment	30/04/2025

Locations

Countries of recruitment

United Kingdom
England
Northern Ireland
Scotland
Wales

Study participating centres

Royal Liverpool University Hospital

Liverpool University Hospital NHS Foundation Trust
Liverpool
L7 8XP
United Kingdom

Altnagelvin Area Hospital

Glenshane Road
Londonderry
BT47 6SB
United Kingdom

Antrim Area Hospital

45 Bush Rd
Antrim
BT41 2RL
United Kingdom

Barnsley District General Hospital

Pogmoor Road
Barnsley
S75 2EP
United Kingdom

Queen Elizabeth Hospital

University Hospitals Birmingham NHS Foundation Trust
Birmingham
B15 2GW
United Kingdom

Bristol Royal Infirmary

Marlborough Street
Bristol
BS2 8HW
United Kingdom

Royal Infirmary of Edinburgh

51 Little France Crescent
Old Dalkeith Road
Edinburgh
Lothian
EH16 4SA
United Kingdom

Freeman Hospital

Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle upon Tyne
NE7 7DN
United Kingdom

The Royal Victoria Infirmary

Queen Victoria Road
Newcastle upon Tyne
TS1 4LP
United Kingdom

Glasgow Royal Infirmary

84 Castle Street
Glasgow
G4 0SF
United Kingdom

Gloucester Royal Hospital

Great Western Road
Gloucester
GL1 3NN
United Kingdom

Guy's Hospital

Guy's and St Thomas' NHS Foundation Trust
London
SE1 9RT
United Kingdom

St Thomas' Hospital

Guy's and St Thomas' NHS Foundation Trust
London
SE1 7EH
United Kingdom

Hull Royal Infirmary

Hull University Teaching Hospitals NHS Trust
Hull
HU3 2JZ
United Kingdom

James Cook University Hospital

South Tees Hospitals NHS Foundation Trust
Middlesbrough
TS4 3BW
United Kingdom

King's College Hospital

King's College Hospital NHS Foundation Trust
London
SE5 9RS
United Kingdom

Leicester Royal Infirmary

University Hospitals of Leicester NHS Trust
Leicester
LE1 5WW
United Kingdom

Medway Maritime Hospital

Medway NHS Foundation Trust
Gillingham
ME7 5NY
United Kingdom

Morriston Hospital NHS Trust

Heol Maes Eglwys
Morriston
Swansea
SA6 6NL
United Kingdom

Musgrove Park Hospital

Somerset NHS Foundation Trust
Taunton
TA1 5DA
United Kingdom

Queen's Medical Centre

Nottingham University Hospital NHS Trust
Nottingham
NG7 2UH
United Kingdom

Pinderfields Hospital

The Mid Yorkshire Hospitals NHS Trust
Wakefield
WF1 4DG
United Kingdom

Poole Hospital

University Hospitals Dorset NHS Foundation Trust
Poole
BH15 2JB
United Kingdom

Queen Elizabeth Hospital

Lewisham and Greenwich NHS Trust
London
SE13 6LH
United Kingdom

University Hospital Lewisham

Lewisham and Greenwich NHS Trust
London
SE13 6LH
United Kingdom

Rotherham District General Hospital

The Rotherham NHS Foundation Trust
Rotherham
S60 2UD
United Kingdom

Royal Berkshire Hospital

Royal Berkshire NHS Foundation Trust
Reading
RG1 5AN
United Kingdom

Royal Bournemouth Hospital

Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Royal Cornwall Hospital

Royal Cornwall Hospitals NHS Trust
Truro
TR1 3LJ
United Kingdom

Aintree Hospital

Liverpool University Hospital NHS Foundation Trust
Liverpool
L9 7AL
United Kingdom

The Royal Oldham Hospital

Rochdale Road
Oldham
OL1 2JH
United Kingdom

Royal Stoke University Hospital

University Hospitals of North Midlands NHS Trust
Stoke-on-Trent
ST4 6QG
United Kingdom

Royal United Hospital Bath

Royal United Hospitals Bath NHS Foundation Trust
Bath
BA1 3NG
United Kingdom

Royal Victoria Hospital

Belfast Health and Social Care Trust
Belfast
BT12 6BA
United Kingdom

Salford Royal Hospital

Salford Royal NHS Foundation Trust
Manchester
M6 8HD
United Kingdom

Birmingham City Hospital

Sandwell and West Birmingham Hospitals NHS Trust
Birmingham
B18 7QH
United Kingdom

Southmead Hospital

North Bristol NHS Trust
Bristol
BS10 5NB
United Kingdom

Sunderland Royal Hospital

South Tyneside and Sunderland NHS Foundation Trust
Sunderland
SR4 7TP
United Kingdom

Watford General Hospital

West Hertfordshire Hospitals NHS Trust
Watford
WD18 0HB
United Kingdom

Manchester Royal Infirmary

Manchester University Hospitals NHS Foundation Trust
Manchester
M13 9WL
United Kingdom

York Hospital

York and Scarborough Teaching Hospitals NHS Foundation Trust
York
YO31 8HE
United Kingdom

Royal Hampshire County Hospital

Romsey Road
Winchester
SO22 5DG
United Kingdom

Ipswich Hospital

Heath Road
Ipswich
IP4 5PD
United Kingdom

Royal Preston Hospital

Lancashire Teaching Hospitals NHS Foundation Trust
Preston
PR2 9HT
United Kingdom

Golden Jubilee National Hospital

National Waiting Time Centre Board
Clydebank
G81 4DY
United Kingdom

University Hospital Coventry

University Hospitals Coventry and Warwickshire NHS Trust
Coventry
CV2 2DX
United Kingdom

The Grange University Hospital

Caerleon Road
Cwmbran
NP44 8YN
United Kingdom

Queen Alexandra Hospital

Portsmouth Hospitals NHS Trust
Portsmouth
PO6 3LY
United Kingdom

Wythenshawe Hospital

Manchester University NHS Foundation Trust
Manchester
M23 9LT
United Kingdom

North Manchester General Hospital

Manchester University NHS Foundation Trust
Manchester
M8 5RB
United Kingdom

Belfast City Hospital

Belfast Health and Social Care Trust
Belfast
BT9 7AB
United Kingdom

Sandwell General Hospital

Sandwell and West Birmingham Hospitals NHS Trust
West Bromwich
B71 4HJ
United Kingdom

Addenbrookes Hospital

Hills Road
Cambridge
CB2 0QQ
United Kingdom

Heartlands Hospital

Bordesley Green East
Bordesley Green
Birmingham
B9 5ST
United Kingdom

Chesterfield Royal Hospital

Chesterfield Road
Calow
Chesterfield
S44 5BL
United Kingdom

John Radcliffe Hospital

Headley Way
Headington
Oxford
OX3 9DU
United Kingdom

Victoria Hospital

Hayfield Road
Kirkcaldy
KY2 5AH
United Kingdom

Royal Devon and Exeter Hospital

Royal Devon & Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom

Lincoln County Hospital

Greetwell Road
Lincoln
LN2 5QY
United Kingdom

Queen Elizabeth University Hospital

1345 Govan Road
Glasgow
G51 4TF
United Kingdom

Derriford Hospital

Derriford Road
Plymouth
PL6 8DH
United Kingdom

William Harvey Hospital

Kennington Road
Willesborough
Ashford
TN24 0LZ
United Kingdom

Yeovil District Hospital

Higher Kingston
Yeovil
BA21 4AT
United Kingdom

University Hospital Monklands

Monkscourt Ave
Airdrie
ML6 0JS
United Kingdom

West Suffolk Hospital

Hardwick Lane
Bury St. Edmunds
IP33 2QZ
United Kingdom

Northern General Hospital

Northern General Hospital NHS Trust
C Floor, Huntsmnan Building
Herries Road
Sheffield
S5 7AU
United Kingdom

Royal Hallamshire Hospital

Glossop Road
Sheffield
S10 2JF
United Kingdom

Wrexham Maelor Hospital

Croesnewydd Road
Wrexham Technology Park
Wrexham
LL13 7TD
United Kingdom

Glan Clwd Hospital

Ysbyty Glan Clwydd
Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom

Aberdeen Royal Infirmary

Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom

Bedford Hospital

Kempston Road
Bedford
MK42 9DJ
United Kingdom

University College London Hospital

250 Euston Road
London
NW1 2PG
United Kingdom

Torbay Hospital

Newton Road
Torquay
TQ2 7AA
United Kingdom

Royal Free Hospital

Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom

Warrington Hospital

Lovely Lane
Warrington
WA5 1QG
United Kingdom

Northern Devon District Hospital

Raleigh Park
Barnstaple
EX31 4JB
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
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?
Protocol article		10/04/2025	17/06/2025	Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

02/07/2025: The following changes were made to the trial record:
1. The completion date was changed from 31/07/2025 to 31/10/2025.
2. The total final enrolment was added.
17/06/2025: Publication reference added.
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.