Alpha 2 Agonists for Sedation to Produce Better Outcomes From Critical Illness (A2B Trial)
NCT ID: NCT03653832
Last Updated: 2024-10-03
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE3
1437 participants
INTERVENTIONAL
2018-12-10
2024-07-31
Brief Summary
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The investigators want to know whether starting an alpha2-agonist drug early in ICU can help keep patients more lightly sedated but still comfortable, and whether patients spend less time on the ventilator. The investigators also want to know how safe they are and if they can improve important outcomes during ICU stay and during recovery. The investigators also want to know if they are value for money.
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Detailed Description
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For sedation, most ICUs use a drug called 'propofol' that is good at reducing anxiety and making people sleepy, but is not a pain killer, so additional pain killers are needed. There are two other drugs used less often called 'alpha-2 agonists' that have both sedative and pain-killing 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 investigators want to know 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 investigators also want to know how safe these drugs are and if improve important outcomes during ICU stay can be improved (like delirium, comfort, and safety) and during recovery (like bad memories, anxiety, and depression). The investigators also want to know if they are value for money.
The trial will include 1437 participants needing to be on a ventilator for at least 2 days. Participants will be allocated to one of three groups by chance. One group will continue to receive propofol; one group will receive dexmedetomidine; and one group will receive clonidine. All participants will receive extra pain relief if needed, and participants in the dexmedetomidine and clonidine groups will continue to receive propofol if they need this in addition. Nurses and doctors will alter the doses of sedation drugs to try and reduce or stop them, but always aiming to have participants lightly sedated and comfortable. The trial will compare if participants on dexmedetomidine or clonidine come off the ventilator quicker than those just on propofol. The trial will examine whether there was a difference between the groups in the number of participants who experienced delirium in ICU, compare how comfortable participants were, and measure if participants memories of being in the ICU differed.
Patients who were in the trial will be followed up for up to 180 days afterwards because the investigators want to compare if there were differences in the after-effects of being ill in ICU between the groups. Participants will be asked to complete questionnaires that will assess their memories of the ICU experience at 90 days after entering the trial. At 180 days, participants will be asked to complete questionnaires so that the investigators can detect how patients feel about their quality of life or if they suffer from anxiety, depression or stress. Note that for patients recruited during the final months of recruitment, the 90 and 180 days follow will be truncated and not collected. This was agreed with the TSC and funder to reduce trial costs and enable trial completion.
Alongside this trial, investigators will be looking at value for money, which is important because clonidine, dexmedetomidine, and propofol costs are quite different. Clonidine, in particular, is relatively inexpensive. ICU nurses' and doctors' views on how easy or difficult it was to adjust and use the drugs will be obtained. This will give 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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Dexmedetomidine Group
For dexmedetomidine, 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-1.hour-1 titrated to a maximum dose 1.4 µg.kg-1 hour-1. Lower starting doses will be used at clinical discretion for patients with cardiovascular instability.
Dexmedetomidine
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. Once established, additional propofol will only be used when the maximum α2-agonist dose is reached or because cardiovascular or other side-effects limit dose escalation.
Clonidine Group
For clonidine, the regimen is designed to be equipotent with dexmedetomidine based on known pharmacokinetics and pharmacodynamics. The chosen 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-1.hour-1 titrated to a maximum dose of 2 µg.kg-1.hour-1. Lower starting doses will be used at clinical discretion for patients with cardiovascular instability.
Clonidine
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. Once established, additional propofol will only be used when the maximum α2-agonist dose is reached or because cardiovascular or other side-effects limit dose escalation.
Usual Care (Propofol) Group
Usual Care Group : Patients will continue to receive intravenous propofol according to usual current care . The sedation targets, weaning, and sedation discontinuation procedures will follow the same clinical targets as for the clonidine and dexmedetomidine groups.
Propofol
Patients will continue to receive intravenous propofol according to current usual care.
Interventions
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Dexmedetomidine
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. Once established, additional propofol will only be used when the maximum α2-agonist dose is reached or because cardiovascular or other side-effects limit dose escalation.
Clonidine
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. Once established, additional propofol will only be used when the maximum α2-agonist dose is reached or because cardiovascular or other side-effects limit dose escalation.
Propofol
Patients will continue to receive intravenous propofol according to current usual care.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Aged 18 or over
3. Within 48 hours of first episode of mechanical ventilation 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
Exclusion Criteria
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
18. Patient known to have experienced a period with heart rate \<50 beats per minute for 60 minutes or longer since commencing mechanical ventilation in the ICU
18 Years
ALL
No
Sponsors
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West Hertfordshire Hospitals NHS Trust
OTHER
Queen's University, Belfast
OTHER
The University of Queensland
OTHER
University Hospital of Wales
OTHER
Edinburgh Napier University
OTHER
King's College London
OTHER
University of Warwick
OTHER
University of Manchester
OTHER
Royal Surrey County Hospital NHS Foundation Trust
OTHER
University College, London
OTHER
NHS Lothian
OTHER_GOV
Imperial College London
OTHER
University of Cambridge
OTHER
University of Edinburgh
OTHER
Responsible Party
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Principal Investigators
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Timothy Walsh, MBChB MD MSc
Role: PRINCIPAL_INVESTIGATOR
University of Edinburgh
Locations
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Belfast Health & Social Care Trust
Belfast, , United Kingdom
South Eastern Health and Social Trust
Belfast, , United Kingdom
University Hospitals Birmingham NHS Foundation Trust
Birmingham, , United Kingdom
Blackpool Teaching Hospitals NHS Foundation Trust
Blackpool, , United Kingdom
North Bristol NHS Trust
Bristol, , United Kingdom
University Hospitals Bristol NHS Foundation Trust
Bristol, , United Kingdom
Cambridge University Hospitals NHS Foundation Trust
Cambridge, , United Kingdom
Cardiff and Vale University Health Board
Cardiff, , United Kingdom
Countess of Chester Hospital NHS Foundation Trust
Chester, , United Kingdom
The Dudley Group NHS Foundation Trust
Dudley, , United Kingdom
NHS Dumfries and Galloway
Dumfries, , United Kingdom
NHS Lothian
Edinburgh, , United Kingdom
Medway NHS Foundation Trust
Gillingham, , United Kingdom
NHS Greater Glasgow and Clyde
Glasgow, , United Kingdom
Harrogate and District NHS Trust
Harrogate, , United Kingdom
Wye Valley NHS Trust
Hereford, , United Kingdom
The Queen Elizabeth Hospital Kings Lynn NHS Foundation Trust
Kings Lynn, , United Kingdom
Leeds Teaching Hospitals NHS Trust
Leeds, , United Kingdom
University Hospitals of Leicester
Leicester, , United Kingdom
Lewisham and Greenwich NHS Trust
Lewisham, , United Kingdom
Aintree University Hospital Foundation Trust
Liverpool, , United Kingdom
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Liverpool, , United Kingdom
Guys and St Thomas NHS Foundation Trust
London, , United Kingdom
Imperial College Healthcare NHS Trust
London, , United Kingdom
King's College Hospital NHS Foundation Trust
London, , United Kingdom
St George's University Hospitals NHS Foundation Trust
London, , United Kingdom
The Royal Marsden NHS Foundation Trust
London, , United Kingdom
University College London Hospitals NHS Foundation Trust
London, , United Kingdom
Manchester University Foundation Trust
Manchester, , United Kingdom
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle, , United Kingdom
Aneurin Bevan University Health Board
Newport, , United Kingdom
Nottingham University Hospitals NHS Trust
Nottingham, , United Kingdom
Oxford University Hospitals NHS Foundation Trust.
Oxford, , United Kingdom
Poole Hospitals NHS Foundation Trust
Poole, , United Kingdom
University Hospital Southampton NHSFT
Southampton, , United Kingdom
North Tees and Hartlepool NHS Foundation Trust
Stockton-on-Tees, , United Kingdom
Taunton and Somerset NHS Foundation Trust
Taunton, , United Kingdom
West Hertfordshire Hospitals NHS Trust
Watford, , United Kingdom
Countries
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References
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Walsh TS, Parker RA, Aitken LM, McKenzie CA, Emerson L, Boyd J, Macdonald A, Beveridge G, Giddings A, Hope D, Irvine S, Tuck S, Lone NI, Kydonaki K, Norrie J, Brealey D, Antcliffe D, Reay M, Williams A, Bewley J, Creagh-Brown B, McAuley DF, Dark P, Wise MP, Gordon AC, Perkins GD, Reade MC, Blackwood B, MacLullich A, Glen R, Page VJ, Weir CJ; A2B Trial Investigators. Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients: The A2B Randomized Clinical Trial. JAMA. 2025 Jul 1;334(1):32-45. doi: 10.1001/jama.2025.7200.
Aitken LM, Emerson LM, Kydonaki K, Blackwood B, Creagh-Brown B, Lone NI, McKenzie CA, Reade MC, Weir CJ, Wise MP, Walsh TS. Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B trial): protocol for a mixed-methods process evaluation of a randomised controlled trial. BMJ Open. 2024 Apr 5;14(4):e081637. doi: 10.1136/bmjopen-2023-081637.
Walsh TS, Aitken LM, McKenzie CA, Boyd J, Macdonald A, Giddings A, Hope D, Norrie J, Weir C, Parker RA, Lone NI, Emerson L, Kydonaki K, Creagh-Brown B, Morris S, McAuley DF, Dark P, Wise MP, Gordon AC, Perkins G, Reade M, Blackwood B, MacLullich A, Glen R, Page VJ. Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK. BMJ Open. 2023 Dec 10;13(12):e078645. doi: 10.1136/bmjopen-2023-078645.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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HTA 16/93/01
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
2018-001650-98
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
243640
Identifier Type: OTHER
Identifier Source: secondary_id
18/SS/0085
Identifier Type: OTHER
Identifier Source: secondary_id
AC18022
Identifier Type: -
Identifier Source: org_study_id
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