A2B – a study investigating the effect of different types of sedation on the length of time critically ill patients require ventilation in intensive care

ISRCTN	ISRCTN18035454
DOI	https://doi.org/10.1186/ISRCTN18035454
ClinicalTrials.gov (NCT)	NCT03653832
Clinical Trials Information System (CTIS)	2018-001650-98
Integrated Research Application System (IRAS)	243640
Protocol serial number	HTA 16/93/01, IRAS 243640
Sponsor	Academic and Clinical Central Office for Research and Development (ACCORD)
Funder	Health Technology Assessment Programme

Submission date: 23/10/2018
Registration date: 25/10/2018
Last edited: 04/07/2025

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

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Many patients in intensive care (ICU) need help to breathe on a breathing machine and need pain killers and sedatives to keep them comfortable and pain-free. However, keeping patients too deeply sedated can make their ICU stay longer, can cause ICU confusion (delirium), and afterwards may cause distressing memories. Ideally, we want to keep patients less sedated, but it is difficult to get the balance of sedation and comfort right. For sedation, most ICUs use a drug called propofol that is good at reducing anxiety and making people sleepy, but is not a painkiller, so additional painkillers are needed. There are two other drugs used less often called alpha-2 agonists that have both sedative and painkilling actions, which may make it easier for patients to be more awake and comfortable on the ventilator. The two drugs are called clonidine and dexmedetomidine. The aim of this study is to find out whether starting an alpha2-agonist drug early in ICU, and using this instead of propofol as much as possible, can help keep patients more lightly sedated but still comfortable, and whether patients spend less time on the ventilator with these drugs. The researchers also want to find out how safe they are, if they can improve important outcomes during ICU stay (like delirium, comfort, and safety) and during recovery (like bad memories, anxiety, and depression), and if they are value for money.

Who can participate?
Patients aged 18 years and over who need to be on a ventilator for at least 2 days

What does the study involve?
Patients are randomly allocated to one of three groups. One group continues to receive propofol, one group receives dexmedetomidine, and one group receives clonidine. All patients receive extra pain relief if needed, and patients in the dexmedetomidine and clonidine groups continue to receive propofol if they need this in addition. Nurses and doctors alter the doses of sedation drugs to try and reduce or stop them, but always aiming to have patients lightly sedated and comfortable. The study assesses whether patients on dexmedetomidine or clonidine come off the ventilator quicker than those just on propofol, and looks at whether there is a difference between the groups in the number of people who experience delirium in ICU, how comfortable people are, and whether participants’ memories of being in the ICU differed. Participants are followed up for 180 days afterwards to see if there are differences in the after-effects of being ill in ICU between the groups. Participants complete questionnaires to assess their memories of the ICU experience at 90 days after entering the trial. At 180 days, they also complete questionnaires about their quality of life or if they suffer from anxiety, depression or stress. Value for money is important because the costs of clonidine, dexmedetomidine, and propofol are quite different. Clonidine, in particular, is relatively inexpensive. ICU nurses’ and doctors’ views are collected on how easy or difficult it was to adjust and use the drugs, to provide valuable practical information that can be shared with other ICUs, particularly if alpha2-agonists are found to be better and other ICUs want to start using them. [Note that for participants recruited in the final months of trial recruitment, the 90- and 180-day follow-up will be truncated and not collected. This was agreed with the TSC and funder to reduce trial costs and enable trial completion.]

What are the possible benefits and risks of participating?
There are no direct benefits to taking part in the trial but it may help to improve outcomes for patients requiring treatment with a ventilator in ICU in the future. As the sedative drugs being used in this study are commonly used drugs, the potential risk to patients on the trial is similar to the potential risk of patients on ventilation and sedative therapy who are not in the trial.

Where is the study run from?
The University of Edinburgh (UK)

When is the study starting and how long is it expected to run for?
April 2018 to July 2024

Who is funding the study?
The NIHR Health Technology Assessment Programme (UK)

Who is the main contact?
1. Sian Irvine, sian.irvine@ed.ac.uk
2. Prof. Timothy Walsh, timothy.walsh@ed.ac.uk

Contact information

Dr Sian Irvine
Public

Edinburgh Clinical Trials Unit
Usher Building, University of Edinburgh
5-7 Little France Road, Edinburgh BioQuarter - Gate 3
Edinburgh
EH16 4UX
United Kingdom

ORCID ID	0000-0001-9352-4951
Email	A2B@ed.ac.uk

Prof Timothy Walsh
Scientific

Dept of Anaesthetics
Critical Care & Pain Medicine
Room S8208, 2nd floor
Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom

ORCID ID	0000-0002-3590-8540
Phone	+44 (0)1312423137
Email	timothy.walsh@ed.ac.uk

Study information

Primary study design	Interventional
Study design	Randomized, parallel-group, allocation concealed, controlled, open-label, phase III, pragmatic, clinical and cost-effectiveness multi-centre trial with an internal pilot
Secondary study design	Randomised parallel trial
Study type	Participant information sheet
Scientific title	Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): a randomised, parallel-group, allocation concealed, controlled, open, Phase III pragmatic clinical and cost-effectiveness trial with internal pilot
Study acronym	A2B
Study objectives	The primary hypothesis is that sedation with α2-agonists decreases the time to extubation in adult mechanically ventilated ICU patients compared with usual care.
Ethics approval(s)	Approved 21/08/2018, Scotland A Research Ethics Committee (2nd Floor, Waverley Gate, 2-4 Waterloo Place, Edinburgh, EH1 3EG, United Kingdom; +44 (0)131 465 5680; manx.neill@nhslothian.scot.nhs.uk), ref: 18/SS/0085
Health condition(s) or problem(s) studied	Critically ill intensive care patients receiving mechanical ventilation
Intervention	Patients will be allocated in a 1:1:1 ratio to the three trial groups detailed below using permuted blocks (randomly arranged sizes of 3, 6, 9, 12) stratified by centre using a remote web-based randomisation system: 1. Dexmedetomidine - dosing regimen - the regimen will follow the manufacturer’s guidance and regimens used in previous trials. Dexmedetomidine will be up and down titrated against sedation targets set by clinical staff and reviewed at regular intervals, and documented at least daily. No loading dose will be administered. The starting dose will be 0.7 μg/kg/hour titrated to a maximum dose 1.4 μg/kg/hour. Lower starting doses will be used at clinical discretion for patients with cardiovascular instability. 2. Clonidine – dosing regimen is similar to that currently used in many UK ICUs as part of routine ‘off label’ practice. Clonidine will be up and down titrated against sedation targets set by clinical staff and reviewed at regular intervals, and at least daily. No loading dose will be administered. The starting dose will be 1.0 μg/kg/hour titrated to a maximum dose of 2.0 μg/kg/hour. 3. Propofol (usual care) – dosing regimen - participants will continue to receive intravenous propofol according to current usual care. The sedation targets, weaning, and sedation discontinuation procedures will follow the same clinical targets as for the clonidine and dexmedetomidine groups. Patients will commence intravenous infusion of open-label study drug according to a weight-based dose regimen as early as possible post randomisation, and within a maximum of 2 h. Bedside clinical staff will transition patients to achieve sedation with the allocated α2-agonist agent as quickly as clinically feasible and safe, to replicate the way these drugs would be used in routine practice. Additional opiate will be used for analgesia using clinical judgement. The intervention period will continue until the patient is weaned from MV and sedation in the ICU. The timing of discontinuation of sedative agents will be at the discretion of the clinical team.
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Dexmedetomidine, clonidine, propofol
Primary outcome measure(s)	Time to successful extubation post-randomisation (hours). A successful first extubation from mechanical ventilation will be defined as follows: 1. From endotracheal extubation: time of first extubation that is followed by 48 hours of spontaneous breathing 2. From tracheostomy: time of extubation will be defined as the first time a patient receives support not exceeding 5 cmH2O CPAP with less or equal to pressure support ventilation of 5cmH2O for a continuous period of 48 hours Added 30/07/2024: 3. From non-invasive mechanical ventilation (NIV): time of extubation will be the start time of the first period during which a patient receives support not exceeding 5 cmH2O CPAP via mask/hood for a continuous period of 48 hours. NIV patients receiving any pressure-supported breaths will not be considered to be spontaneously breathing unassisted. Timepoints: Time of randomisation and time of successful extubation
Key secondary outcome measure(s)	Current secondary outcome measures as of 09/03/2022: 1. Length of ICU stay (number of days). ICU status will be recorded daily from the date of randomisation until the date of ICU discharge, or 180 days, whichever comes first 2. Delirium during ICU stay, assessed twice daily during ICU stay using the Confusion-Agitation method for ICU (CAM-ICU). Delirium will be assessed from the date of randomisation until the date of ICU discharge, or 28 days, whichever comes first 3. Duration of delirium during ICU stay. Delirium will be assessed twice daily during ICU stay using the Confusion-Agitation method for ICU (CAM-ICU). Delirium will be assessed from the date of randomisation until the date of ICU discharge, or 28 days, whichever comes first 4. Sedation quality measured by Richmond Agitation and Sedation Scale (RASS) 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 5. Sedation quality measured by Sedation Quality Assessment Tool (SQAT) daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 6. Analgesia quality measured by Richmond Agitation and Sedation Scale (RASS) 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 7. Analgesia quality measured by Sedation Quality Assessment Tool (SQAT) daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 8. Number of hours to first optimum sedation as measured by a RASS score of -2 or greater. Level of sedation will be assessed 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 9. Number of days to first optimum sedation as assessed by the Sedation Quality Assessment Tool (SQAT). Level of sedation will be assessed daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 10. Ability to communicate pain. Binary assessment by bedside nurse twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 11. Ability to co-operate with care. Binary assessment by bedside nurse twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 12. Relative/Partner/Friend (PerLR) assessment of wakefulness. Response to verbal question, assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 13. Relative/Partner/Friend (PerLR) assessment of patient comfort. Response to verbal question, assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 14. Relative/Partner/Friend (PerLR) assessment of patient communication. Response to verbal question, assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 15. Incidence of drug-related adverse events (bradycardia, hypotension, hypertension, cardiac arrhythmias, cardiac arrest) as documented in the medical records recorded daily from the date of randomisation until the date of documented successful extubation, or 28 days, whichever comes first 16. Incidence of mortality, as documented in the medical records from the date of randomisation until the date of the last follow-up visit at 180 days 17. Patient experience of ICU care measured by Intensive Care Experience Questionnaire at 90 days post ICU discharge 18. Occurrence of anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) questionnaire at 180 days post ICU discharge 19. Occurrence of post-traumatic stress measured by Impact of Events Scale-revised (IES-R) at 180 days post ICU discharge 20. Cognitive function assessed using the Montreal Cognitive Assessment Tool (Postal or Telephone) at 180 days post ICU discharge 21. Health-related quality of life (recalled) assessed by EuroQol tool (EQ-5D-5L) at 30 days post ICU discharge - recalled prior to hospital admission 22. Health-related quality of life (30 day) assessed by EuroQol tool (EQ-5D-5L) at 30 days post ICU discharge 23. Health-related quality of life (90 day) assessed by EuroQol tool (EQ-5D-5L) at 90 days post ICU discharge 24. Health-related quality of life (180 day) assessed by EuroQol tool (EQ-5D-5L) at 180 days post ICU discharge Previous secondary outcome measures: 1. Length of ICU stay (number of days). ICU status will be recorded daily from the date of randomisation until the date of ICU discharge, or 180 days, whichever comes first 2. Delirium during ICU stay, assessed twice daily during ICU stay using the Confusion-Agitation method for ICU (CAM-ICU). Delirium will be assessed from the date of randomisation until the date of ICU discharge, or 28 days, whichever comes first 3. Duration of delirium during ICU stay. Delirium will be assessed twice daily during ICU stay using the Confusion-Agitation method for ICU (CAM-ICU). Delirium will be assessed from the date of randomisation until the date of ICU discharge, or 28 days, whichever comes first 4. Sedation quality measured by Richmond Agitation and Sedation Scale (RASS) 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 5. Sedation quality measured by Sedation Quality Assessment Tool (SQAT) daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 6. Analgesia quality measured by Richmond Agitation and Sedation Scale (RASS) 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 7. Analgesia quality measured by Sedation Quality Assessment Tool (SQAT) daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 8. Number of hours to first optimum sedation as measured by a RASS score of -2 or greater. Level of sedation will be assessed 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 9. Number of days to first optimum sedation as assessed by the Sedation Quality Assessment Tool (SQAT). Level of sedation will be assessed daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 10. Ability to communicate pain. Binary assessment by bedside nurse twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 11. Ability to co-operate with care. Binary assessment by bedside nurse twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 12. Relative/Partner/Friend (PerLR) assessment of wakefulness. Response to verbal question, assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 13. Relative/Partner/Friend (PerLR) assessment of patient comfort. Response to verbal question, assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 14. Relative/Partner/Friend (PerLR) assessment of patient communication. Response to verbal question, assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first 15. Incidence of drug-related adverse events (bradycardia, hypotension, hypertension, cardiac arrhythmias, cardiac arrest) as documented in the medical records recorded daily from the date of randomisation until the date of documented successful extubation, or 28 days, whichever comes first 16. Incidence of mortality, as documented in the medical records from the date of randomisation until the date of the last follow-up visit at 180 days 17. Patient experience of ICU care, measured by Intensive Care Experience Questionnaire at 30 days post ICU discharge 18. Patient experience of ICU care measured by Intensive Care Experience Questionnaire at 90 days post ICU discharge 19. Occurrence of anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) questionnaire at 90 days post ICU discharge 20. Occurrence of anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) questionnaire at 180 days post ICU discharge 21. Occurrence of post-traumatic stress measured by Impact of Events Scale-revised (IES-R) at 90 days post ICU discharge 22. Occurrence of post-traumatic stress measured by Impact of Events Scale-revised (IES-R) at 180 days post ICU discharge 23. Cognitive function assessed using the Montreal Cognitive Assessment Tool (Postal or Telephone) at 90 days post ICU discharge 24. Cognitive function assessed using the Montreal Cognitive Assessment Tool (Postal or Telephone) at 180 days post ICU discharge 25. Health-related quality of life (recalled) assessed by EuroQol tool (EQ-5D-5L) at 30 days post ICU discharge - recalled prior to hospital admission 26. Health-related quality of life (30 day) assessed by EuroQol tool (EQ-5D-5L) at 30 days post ICU discharge 27. Health-related quality of life (90 day) assessed by EuroQol tool (EQ-5D-5L) at 90 days post ICU discharge 28. Health-related quality of life (180 day) assessed by EuroQol tool (EQ-5D-5L) at 180 days post ICU discharge
Completion date	31/07/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	1437
Total final enrolment	1437
Key inclusion criteria	Current participant inclusion criteria as of 22/06/2020: 1. Patient requiring mechanical ventilation (MV) in an ICU 2. Aged 18 years or over 3. Within 48 h of first episode of MV in ICU 4. Requiring sedation with propofol 5. Expected to require a total of 48 hours of MV or more in ICU 6. Expected to require a further 24 hours of MV or more at the time of randomisation in the opinion of the responsible clinician _____ Previous inclusion criteria: 1. Patient requiring mechanical ventilation (MV) in an ICU 2. Aged 18 or over 3. Within 48 hours of starting MV in an ICU 4. Requiring sedation with propofol 5. Expected to require a total of 48 hours of MV or more in ICU 6. Expected to require a further 24 hours of MV or more at the time of randomisation in the opinion of the responsible clinician
Key exclusion criteria	Current exclusion criteria as of 22/06/2020: 1. Acute brain injury (traumatic brain injury; intracranial haemorrhage; ischaemic brain injury from stroke or hypoperfusion) 2. Post-cardiac arrest (where there is clinical concern about hypoxic brain injury) 3. Status epilepticus 4. Continuous therapeutic neuromuscular paralysis at the time of screening or randomisation 5. Guillain-Barre Syndrome 6. Myasthenia gravis 7. Home ventilation 8. Fulminant hepatic failure 9. Patient not expected to survive 24 h by responsible clinician 10. Decision to provide only palliative or end-of-life care 11. Pregnancy 12. Known allergy to one of the study drugs 13. Untreated second or third degree heart block 14. Transferred from another Intensive Care Unit in which MV occurred for >6 h 15. Prisoners 16. Enrolled on another CTIMP 17. Previously enrolled on the A2B Trial 18. Patients with bradycardia: a heart rate of <50 bpm for a period of 60 min or longer since starting MV in the ICU Previous exclusion criteria: 1. Acute brain injury (traumatic brain injury; intracranial haemorrhage; ischaemic brain injury from stroke or hypoperfusion) 2. Post-cardiac arrest (where there is clinical concern about hypoxic brain injury) 3. Status epilepticus 4. Continuous therapeutic neuromuscular paralysis at the time of screening or randomisation 5. Guillain-Barre Syndrome 6. Myasthenia gravis 7. Home ventilation 8. Fulminant hepatic failure 9. Patient not expected to survive 24 hours by responsible clinician 10. Decision to provide only palliative or end-of-life care 11. Pregnancy 12. Known allergy to one of the study drugs 13. Untreated second or third degree heart block 14. Transferred from another Intensive Care Unit in which MV occurred for >6 hours 15. Prisoners 16. Enrolled on another CTIMP 17. Previously enrolled on the A2B Trial
Date of first enrolment	30/09/2018
Date of final enrolment	31/10/2023

Locations

Countries of recruitment

United Kingdom
England
Northern Ireland
Scotland
Wales

Study participating centres

NHS Lothian

The Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom

Belfast Health and Social Care Trust

Royal Victoria Hospital
274 Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Blackpool Teaching Hospitals NHS Foundation Trust

Victoria Hospital
Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Leeds Teaching Hospitals NHS Trust

St James University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

St George's University Hospitals NHS Foundation Trust

St George's Hospital
Blackshaw Road
Tooting
London
SW17 0QT
United Kingdom

North Bristol NHS Trust

Southmead Hospital
Southmead Road
Westbury-On Trym
Bristol
BS10 5NB
United Kingdom

Poole Hospitals NHS Foundation Trust

Poole Hospital
Longfleet Road
Poole
BH15 2JB
United Kingdom

King's College Hospital NHS Foundation Trust

King's College Hospital
Denmark Hill
Brixton
London
SE5 9RS
United Kingdom

Lewisham and Greenwich NHS Trust

University Hospital Lewisham
Lewisham High Street
London
SE13 6LH
United Kingdom

West Hertfordshire Hospitals NHS Trust

Watford General Hospital
Vicarage Road
Watford
WD18 0HB
United Kingdom

Cardiff and Vale University Health Board

University Hospital of Wales
Heath Park
Cardiff
CF14 4XW
United Kingdom

NHS Greater Glasgow and Clyde

Royal Alexandra Hospital
Corsebar Road
Paisley
PA2 9PN
United Kingdom

Countess of Chester Hospital NHS Foundation Trust

Countess of Chester Hospital
Liverpool Road
Chester
CH2 1UL
United Kingdom

Cambridge University Hospitals NHS Foundation Trust

Addenbrooke's Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

North Tees and Hartlepool NHS Foundation Trust

University Hospital of Hartlepool
Holdforth Road
Hartlepool
TS24 9AH
United Kingdom

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle Freeman Hospital
Freeman Road
High Heaton
Newcastle-upon-Tyne
NE7 7DN
United Kingdom

The Royal Marsden NHS Foundation Trust

Royal Marsden Hospital
Fulham Road
London
SW3 6JJ
United Kingdom

Imperial College Healthcare NHS Trust

St Mary's Hospital
Praed Street
London
W2 1NY
United Kingdom

Southampton General Hospital

University Hospital Southampton NHSFT
Tremona Road
Southampton
SO16 6YD
United Kingdom

Leicester Royal Infirmary

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

John Radcliffe Hospital

Oxford University Hospitals NHS Foundation Trust
Headley Way
Oxford
OX3 9DU
United Kingdom

Harrogate District Hospital

Harrogate and District NHS Foundation Trust
Lancaster Park Road
Harrogate
HG2 7SX
United Kingdom

Musgrove Park Hospital

Taunton and Somerset NHS Foundation Trust
Parkfield Road
Taunton
TA1 5DA
United Kingdom

Manchester Royal Infirmary

Manchester University NHS Foundation Trust
Oxford Road
Manchester
M13 9WL
United Kingdom

Heartlands Hospital

University Hospitals Birmingham NHS Foundation Trust
Bordesley Green East
Birmingham
B9 5SS
United Kingdom

Queen Elizabeth Hospital

The Queen Elizabeth Hospital Kings Lynn NHS Foundation Trust
Gayton Road
Kings Lynn
PE30 4ET
United Kingdom

Queens Medical Centre

Nottingham University Hospitals NHS Trust
Derby Road
Nottingham
NG7 2UH
United Kingdom

Medway Maritime Hospital

Medway NHS Foundation Trust
Windmill Road
Gillingham
ME7 5NY
United Kingdom

University College Hospital

University College London Hospitals NHS Foundation Trust
235 Euston Road
London
NW1 2BU
United Kingdom

Russells Hall Hospital

The Dudley Group NHS Foundation Trust
Dudley
DY1 2HQ
United Kingdom

Bristol Royal Infirmary

University Hospitals Bristol NHS Foundation Trust
Bristol
BS2 8HW
United Kingdom

Aintree University Hospital

Aintree University Hospital Foundation Trust
Lower Lane
Liverpool
L9 7AL
United Kingdom

Royal Gwent Hospital

Aneurin Bevan University Health Board
Cardiff Road
Newport
NP20 2UB
United Kingdom

Altnagelvin Area Hospital

Western Health and Social Care Trust
Glenshane Road
Londonderry
BT47 6SB
United Kingdom

NHS Dumfries and Galloway

Grierson House
The Crichton
Bankend Road
Dumfries
DG1 4ZG
United Kingdom

Liverpool University Hospitals NHS Foundation Trust

Royal Liverpool University Hospital
Prescot Street
Liverpool
L7 8XP
United Kingdom

Guy's & St Thomas Hospital

Westminster Bridge Road
London
SE1 7EH
United Kingdom

South Eastern Health and Social Care Trust

Trust Headquarters Ulster Hospital
Upper Newtownards Road
Dundonald
Belfast
BT16 1RH
United Kingdom

Wye Valley NHS Trust

County Hospital
27 Union Walk
Hereford
HR1 2ER
United Kingdom

Western General Hospital

Crewe Road South
Edinburgh
Lothian
EH4 2XU
United Kingdom

Charing Cross Hospital

Fulham Palace Road
London
W6 8RF
United Kingdom

Hammersmith Hospitals NHS Trust

Hammersmith Hospital
Du Cane Road
London
W12 0HS
United Kingdom

Belfast City Hospital

51 Lisburn Rd
Belfast
BT9 7AB
United Kingdom

The Royal Victoria Infirmary

Queen Victoria Road
Newcastle upon Tyne
TS1 4LP
United Kingdom

Queen Elizabeth University Hospital

1345 Govan Road
Glasgow
G51 4TF
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	Current individual participant data (IPD) sharing statement as of 30/07/2024: The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Tim Walsh (Timothy.Walsh@ed.ac.uk). The data will not be available until around August 2024. Consent was requested from patients to anonymously share their data with other researchers. Current individual participant data (IPD) sharing statement as of 09/03/2022: The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Tim Walsh (Timothy.Walsh@ed.ac.uk). The data will not be available until around June 2023. Consent was requested from patients to anonymously share their data with other researchers. Previous individual participant data (IPD) sharing statement: The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Tim Walsh (Timothy.Walsh@ed.ac.uk). The data will not be available until around August 2022. Consent was requested from patients to anonymously share their data with other researchers.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		19/05/2025	04/07/2025	Yes	No
Protocol article		10/12/2023	30/07/2024	Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version 7.0	25/04/2023	30/07/2024	No	No
Statistical Analysis Plan		27/03/2024	30/07/2024	No	No
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN18035454_PROTOCOL_V7.0_25Apr23.pdf: Protocol file

Editorial Notes

04/07/2025: Publication reference added.
01/10/2024: The plain English summary was updated to reflect previous changes made to the protocol and primary outcome measures.
30/07/2024: The following changes were made to the study record:
1. Protocol uploaded.
2. IRAS number, ethics approval details, publication reference, statistical analysis plan and total final enrolment were added.
3. The study participating centres were updated to remove University Hospitals of Morecambe Bay NHS Foundation Trust, University Hospitals Coventry and Warwickshire NHS Trust, Barking, Havering and Redbridge University Hospitals NHS Trust, Gateshead Health NHS Foundation Trust and NHS Fife, and add Western General Hospital, Charing Cross Hospital, Hammersmith Hospitals NHS Trust, Belfast City Hospital, The Royal Victoria Infirmary and Queen Elizabeth University Hospital.
4. The publication and dissemination plan, contact details and primary outcome measures were updated.
21/11/2023: Contact details updated.
03/08/2023: The following changes have been made:
1. The target number of participants has been changed from 1737 to 1437.
2. The plain English summary has been updated to include a note about participants recruited in the last few months of the recruitment period.
22/02/2023: The following changes have been made:
1. The recruitment end date has been changed from 31/03/2023 to 31/10/2023.
2. The overall trial end date has been changed from 30/09/2023 to 31/07/2024 and the plain English summary updated accordingly.
19/01/2023: The recruitment end date was changed from 31/01/2023 to 31/03/2023.
13/01/2023: A public contact has been changed.
19/10/2022: The recruitment end date was changed from 31/10/2022 to 31/01/2023.
09/03/2022: The following changes have been made:
1. The secondary outcome measures have been updated.
2. The trial participating centres "NHS Dumfries and Galloway", "Liverpool University Hospitals NHS Foundation Trust", "University Hospitals of Morecambe Bay NHS Foundation Trust", "University Hospitals Coventry and Warwickshire NHS Trust", "Guys and St Thomas' NHS Foundation Trust", "Barking, Havering and Redbridge University Hospitals NHS Trust", "South Eastern Health and Social Care Trust", "Gateshead Health NHS Foundation Trust", "NHS Fife", and "Wye Valley NHS Trust" have been added and the trial participating centre "Dorset County Hospital NHS Foundation Trust" has been removed.
3. The individual participant data (IPD) sharing statement has been updated.
21/07/2021: The following changes have been made:
1. The recruitment end date has been changed from 30/07/2021 to 31/10/2022.
2. The overall trial end date has been changed from 31/12/2021 to 30/09/2023 and the plain English summary has been updated to reflect this change.
3. The intention to publish date has been changed from 30/12/2022 to 30/09/2024.
20/01/2021: The recruitment end date was changed from 30/01/2021 to 30/07/2021.
22/06/2020: The following changes have been made:
1. The participant inclusion criteria have been changed.
2. The participant exclusion criteria have been changed.
3. Southampton General Hospital, Leicester Royal Infirmary, John Radcliffe Hospital, Harrogate District Hospital, Musgrove Park Hospital, Manchester Royal Infirmary, Heartlands Hospital, Queen Elizabeth Hospital, Queens Medical Centre, Medway Maritime Hospital, University College Hospital, Russells Hall Hospital, Bristol Royal Infirmary, Aintree University Hospital, Royal Gwent Hospital and Altnagelvin Area Hospital have been added to the trial participating centres.
4. The plain English summary has been updated to clarify where the study is managed from.