Condition category
Not Applicable
Date applied
23/10/2018
Date assigned
25/10/2018
Last edited
22/06/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

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 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 30 and 90 days after entering the trial. At 90 and 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.

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 December 2021

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

Who is the main contact?
1. Dr Julia Boyd
julia.boyd@ed.ac.uk
2. Prof. Timothy Walsh
timothy.walsh@ed.ac.uk

Trial website

https://www.ed.ac.uk/usher/edinburgh-clinical-trials/our-studies/all-current-studies

Contact information

Type

Public

Primary contact

Dr Julia Boyd

ORCID ID

Contact details

Edinburgh Clinical Trials Unit
Usher Institute
The University of Edinburgh
Nine Edinburgh BioQuarter
9 Little France Road
Edinburgh
EH16 4UX
United Kingdom
+44 (0)131 651 9908
julia.boyd@ed.ac.uk

Type

Scientific

Additional contact

Prof Timothy Walsh

ORCID ID

Contact details

Dept of Anaesthetics
Critical Care & Pain Medicine
Room S8208
2nd floor
Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom
+44 (0)1312423137
timothy.walsh@ed.ac.uk

Additional identifiers

EudraCT number

2018-001650-98

ClinicalTrials.gov number

NCT03653832

Protocol/serial number

HTA 16/93/01

Study information

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 3 pragmatic clinical and cost-effectiveness
trial with internal pilot

Acronym

A2B

Study hypothesis

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

Scotland A Research Ethics Committee Research Ethics Service, 21/08/2018, REC ref: 18/SS/0085

Study design

Randomised, parallel-group, allocation concealed, controlled, open-label, phase 3, pragmatic, clinical and cost-effectiveness multi-centre trial with an internal pilot

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

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 0.7μg/kg/hour titrated to a maximum dose 1.4μg/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 1.0μg/kg/hour titrated to a maximum dose of 2.0μg/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 two hours. 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 names

Dexmedetomidine, clonidine, propofol

Primary outcome measure

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
Timepoints: Time of randomisation and time of successful extubation

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

Overall trial start date

01/04/2018

Overall trial end date

31/12/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 22/06/2020:
1. Patient requiring mechanical ventilation (MV) in an ICU
2. Aged 18 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

1737

Participant 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

Recruitment start date

30/09/2018

Recruitment end date

30/01/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

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

Trial participating centre

Belfast Health and Social Care Trust
Royal Victoria Hospital 274 Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Trial participating centre

Dorset County Hospital NHS Foundation Trust
Dorset County Hospital Williams Avenue
Dorchester
DT1 2JY
United Kingdom

Trial participating centre

Blackpool Teaching Hospitals NHS Foundation Trust
Victoria Hospital Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
St James University Hospital Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

St George's University Hospitals NHS Foundation Trust
St George's Hospital Blackshaw Road Tooting
London
SW17 0QT
United Kingdom

Trial participating centre

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

Trial participating centre

Poole Hospitals NHS Foundation Trust
Poole Hospital Longfleet Road
Poole
BH15 2JB
United Kingdom

Trial participating centre

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

Trial participating centre

Lewisham and Greenwich NHS Trust
University Hospital Lewisham Lewisham High Street
London
SE13 6LH
United Kingdom

Trial participating centre

West Hertfordshire Hospitals NHS Trust
Watford General Hospital Vicarage Road
Watford
WD18 0HB
United Kingdom

Trial participating centre

Cardiff and Vale University Health Board
University Hospital of Wales Heath Park
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
Royal Alexandra Hospital Corsebar Road
Paisley
PA2 9PN
United Kingdom

Trial participating centre

Countess of Chester Hospital NHS Foundation Trust
Countess of Chester Hospital Liverpool Road
Chester
CH2 1UL
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
Addenbrooke's Hospital Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

North Tees and Hartlepool NHS Foundation Trust
University Hospital of Hartlepool Holdforth Road
Hartlepool
TS24 9AH
United Kingdom

Trial participating centre

The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle Freeman Hospital Freeman Road High Heaton
Newcastle-upon-Tyne
NE7 7DN
United Kingdom

Trial participating centre

The Royal Marsden NHS Foundation Trust
Royal Marsden Hospital Fulham Road
London
SW3 6JJ
United Kingdom

Trial participating centre

Imperial College Healthcare NHS Trust
St Mary's Hospital Praed Street
London
W2 1NY
United Kingdom

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

Russells Hall Hospital
The Dudley Group NHS Foundation Trust
Dudley
DY1 2HQ
United Kingdom

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Trial participating centre

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

Sponsor information

Organisation

Academic and Clinical Central Office for Research and Development (ACCORD)

Sponsor details

Research & Governance
University of Edinburgh
Queen’s Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
+44 (0)131 242 9418
enquiries@accord.scot

Sponsor type

University/education

Website

https://www.accord.scot/

Funders

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The Clinical Study Report (CSR) will be submitted to the Sponsor and REC within 1 year of the end of the study. Where acceptable, a published journal article may be submitted as the CSR. The Chief Investigator will provide the CSR to ACCORD, for review, prior to finalization. The clinical study report may be used for publication and presentation at scientific meetings. Investigators have the right to publish orally or in writing the results of the study. The results of the study, together with other mandated information, will be uploaded to the European clinical trials database within 1 year of the end of the study. Summaries of results will also be made available to Investigators for dissemination within their clinics (where appropriate and according to their discretion). Please contact the study team for any further information or documentation (A2B@ed.ac.uk).

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.

Intention to publish date

30/12/2022

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

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.