Critical IllnessPhase 3A2BNCT03653832
Alpha 2 Agonists for Sedation to Produce Better Outcomes From Critical Illness (A2B Trial)
A Phase 3 study testing Dexmedetomidine, Clonidine and Propofol in people with Critical Illness, run by University of Edinburgh at 38 sites in United Kingdom.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Critical Illness
- What is being tested?
- Dexmedetomidine, Clonidine and Propofol
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,404 participants
- Where
- 38 sitesUnited Kingdom
- Study dates
- 11 Dec 2018to 31 Jul 2024
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patient requiring mechanical ventilation (MV) in an ICU
- Aged 18 or over
- Within 48 hours of first episode of mechanical ventilation in ICU
- Requiring sedation with propofol
- Expected to require a total of 48 hours of MV or more in ICU
- Expected to require a further 24 hours of MV or more at the time of randomisation in the opinion of the responsible clinician
Who cannot join
- Acute brain injury (traumatic brain injury; intracranial haemorrhage; ischaemic brain injury from stroke or hypoperfusion)
- Post-cardiac arrest (where there is clinical concern about hypoxic brain injury)
- Status epilepticus
- Continuous therapeutic neuromuscular paralysis at the time of screening or randomisation
- Guillain-Barre Syndrome
- Myasthenia gravis
Show all 18Show fewer
- Home ventilation
- Fulminant hepatic failure
- Patient not expected to survive 24 hours by responsible clinician
- Decision to provide only palliative or end-of-life care
- Pregnancy
- Known allergy to one of the study drugs
- Untreated second or third degree heart block
- Transferred from another Intensive Care Unit in which MV occurred for >6 hours
- Prisoners
- Enrolled on another CTIMP
- Previously enrolled on the A2B Trial
- 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
Trial locations and contacts
38 sites in 1 country.
38 sites in 1 country
United Kingdom38 sites
Belfast Health & Social Care Trust
Belfast
South Eastern Health and Social Trust
Belfast
University Hospitals Birmingham NHS Foundation Trust
Birmingham
Blackpool Teaching Hospitals NHS Foundation Trust
Blackpool
North Bristol NHS Trust
Bristol
University Hospitals Bristol NHS Foundation Trust
Bristol
Cambridge University Hospitals NHS Foundation Trust
Cambridge
Cardiff and Vale University Health Board
Cardiff
Countess of Chester Hospital NHS Foundation Trust
Chester
The Dudley Group NHS Foundation Trust
Dudley
NHS Dumfries and Galloway
Dumfries
NHS Lothian
Edinburgh
Medway NHS Foundation Trust
Gillingham
NHS Greater Glasgow and Clyde
Glasgow
Harrogate and District NHS Trust
Harrogate
Wye Valley NHS Trust
Hereford
The Queen Elizabeth Hospital Kings Lynn NHS Foundation Trust
Kings Lynn
Leeds Teaching Hospitals NHS Trust
Leeds
University Hospitals of Leicester
Leicester
Lewisham and Greenwich NHS Trust
Lewisham
Aintree University Hospital Foundation Trust
Liverpool
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Liverpool
Guys and St Thomas NHS Foundation Trust
London
Imperial College Healthcare NHS Trust
London
King's College Hospital NHS Foundation Trust
London
St George's University Hospitals NHS Foundation Trust
London
The Royal Marsden NHS Foundation Trust
London
University College London Hospitals NHS Foundation Trust
London
Manchester University Foundation Trust
Manchester
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle
Aneurin Bevan University Health Board
Newport
Nottingham University Hospitals NHS Trust
Nottingham
Oxford University Hospitals NHS Foundation Trust.
Oxford
Poole Hospitals NHS Foundation Trust
Poole
University Hospital Southampton NHSFT
Southampton
North Tees and Hartlepool NHS Foundation Trust
Stockton-on-Tees
Taunton and Somerset NHS Foundation Trust
Taunton
West Hertfordshire Hospitals NHS Trust
Watford
About this study
Official 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
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 patients should be kept less sedated, but it is difficult to get the balance of sedation and comfort right.
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.
Read the detailed description
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, the investigators 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 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
- Critical Illness
- Being tested
- Dexmedetomidine, Clonidine, Propofol
- Keywords
- Sedation, Ventilation
- Medical subject headings
- Critical Illness, Respiratory Aspiration
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DexmedetomidineDrug
Also called Dexdor
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.
ClonidineDrug
Also called Catapres
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.
PropofolDrug
Also called Diprivan
Patients will continue to receive intravenous propofol according to current usual care.
| Study group | Role | What they receive |
|---|---|---|
| Dexmedetomidine Group | Experimental | 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. Receives: Drug: Dexmedetomidine |
| Clonidine Group | Experimental | 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. Receives: Drug: Clonidine |
| Usual Care (Propofol) Group | Active comparator | 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. Receives: Drug: Propofol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to First Successful Extubation Post-randomisation (Hours).
The primary outcome is the time from randomisation to the time of successful extubation (in hours post-randomisation)using an internationally agreed definition
Measured: Ventilation status will be recorded twice daily from the date of randomisation until the date of documented successful extubation, or 180 days, whichever comes first.
Secondary outcomes (26)
Mortality
Mortality data collected from medical records, up to 180 days post-randomisation
Measured: The incidence of death as documented in the medical records will be recorded from the date of randomisation until the date of the last follow-up visit at 180 days.
Duration of ICU Stay
Time from randomisation (days) until ICU discharge or mortality in ICU
Measured: Time from randomisation until ICU discharge or mortality in ICU
Sedation Quality as Measured by Richmond Agitation and Sedation Scale (RASS)
Proportion of patients with highest Richmond Agitation and Sedation Scale (RASS) recorded of -2 or greater. The RASS score measures how sedated or agitated a patient is and ranges from -5 (deeply sedated) to 4 (agitated).
Measured: During ICU stay, up to the occurrence of successful extubation, withdrawal, death, or 28 days post-randomisation, whichever occurred first.
Sedation Quality as Measured by Sedation Quality Assessment Tool (SQAT)
Sedation quality was assessed as measured by the SQAT. We calculated whether there were any days of optimal sedation, agitation, unnecessary deep sedation or pain behaviour during the patient's ICU stay (yes or no). Overall optimum sedation is present when there is no agitation; no unnecessary deep sedation; and no pain behaviour.
Measured: During ICU stay, up to the occurrence of successful extubation, withdrawal, death, or 7 days post-randomisation, whichever occurred first.
Number of Hours Until First Highest RASS of -2 or Greater
Approximate number of hours until first highest Richmond Agitation and Sedation Scale (RASS) recorded of -2 or greater. The RASS score was measured in 12-hour shift periods, and measures how sedated or agitated a patient is and ranges from -5 (deeply sedated) to 4 (agitated).
Measured: During ICU stay, up to the occurrence of successful extubation, withdrawal, death, or 28 days post-randomisation, whichever occurred first.
Number of Days to First Optimum Sedation as Assessed by the Sedation Quality Assessment Tool (SQAT)
Number of days to first optimum sedation as assessed by the Sedation Quality Assessment Tool (SQAT)
Measured: 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.
Delirium During ICU Stay Within the First 10 Days After Randomisation
Did participants have delirium during ICU stay in the 10 days following randomisation? Delirium was assessed by research nurses twice daily during ICU stay using the Confusion-Agitation method for ICU (CAM-ICU).
Measured: During ICU stay, in the first 10 days after randomisation
Duration of Delirium During ICU Stay
How many days did participants have delirium within the first 10 days after randomisation?
Measured: The first 10 days after randomisation during ICU stay
The Number of Patients With Any Pre-specified Drug-related Adverse Events
The number of patients with drug-related adverse events as documented in the medical records - Bradycardia; cardiac arrhythmias; cardiac arrest
Measured: Drug-related adverse events as documented in the medical records were recorded daily from the date of randomisation until the date of documented successful extubation, or 28 days, whichever comes first.
Health - Related Quality of Life - Recalled
Health - related quality of life (recalled) as measured using EuroQol EQ-5D-5L, Visual analogue scale (Health State from 0-100). 100 represents good health and 0 represents death.
Measured: Measured at 30 days - recall Health - related quality of life prior to ICU admission
Health-related Quality of Life (30 Days)
Health - related quality of life as measured using EuroQol EQ-5D-5L, Visual analogue scale (Health State from 0-100). 100 represents good health and 0 represents death.
Measured: Measured at 30 days
Health-related Quality of Life (90 Days)
Health - related quality of life (90 days) as measured using EuroQol EQ-5D-5L, Visual analogue scale (Health State from 0-100). 100 represents good health and 0 represents death.
Measured: Measured at 90 days
Health-related Quality of Life (180 Days)
Health - related quality of life (180 days) as measured using EuroQol EQ-5D-5L, Visual analogue scale (Health State from 0-100). 100 represents good health and 0 represents death.
Measured: Measured at 180 days
Ability to Communicate Pain
Number of participants who were able to communicate pain across any of the 12-hour shift periods, based on assessment by bedside nurses.
Measured: Measured every 12 hours in ICU until primary endpoint reached, assessed up to 30 days post-randomisation.
Ability to Co-operate With Care
Number of participants who were able to co-operate with care across any of the 12-hour shift periods, based on assessment by bedside nurses
Measured: Measured every 12 hours in ICU until primary outcome reached, assessed up to 30 days post-randomisation.
Awareness of Surroundings
Measured using one of the four domains of the Intensive Care Experience Questionnaire (ICE-Q) at 90 days: Awareness of Surroundings (9 items; score range 9-45). Higher scores indicate better awareness of events and surroundings.
Measured: Measured at 90 days
Frightening Experiences
Measured using one of four domains of the Intensive Care Experience Questionnaire (ICE-Q) at 90 days: Frightening Experiences (6 items; score range 6-35). Higher scores indicate more frightening or distressing experiences.
Measured: Measured at 90 days
Recall of Experiences
Measured using one of four domains of the Intensive Care Experience Questionnaire (ICE-Q) at 90 days: Recall of Experiences (5 items; score range 5-25). Higher scores indicate better recall of events.
Measured: Measured at 90 days
Satisfaction With Care
Measured using one of four domains of the Intensive Care Experience Questionnaire (ICE-Q) at 90 days: Satisfaction with Care (4 items; score range 4-20). Higher scores indicate greater satisfaction with ICU care.
Measured: Measured at 90 days
Number of Participants With Any Days of Wakefulness
Participants who were awake on at least one day during mechanical ventilation, as assessed by their Relative/Partner/Friend (PerLR). It was a binary outcome representing any days for which the patient appeared awake to the visitor (yes or no).
Measured: Assessed daily until primary outcome reached, up to 30 days post-randomisation.
Number of Participants With Any Days Appearing Comfortable to the Visitor
Participants who appeared comfortable to the visitor on at least one day during mechanical ventilation, assessed by Relative/Partner/Friend (PerLR). It was a binary outcome representing any days for which the patient appeared comfortable to the visitor (yes or no).
Measured: Assessed daily until primary outcome reached, up to 30 days post-randomisation.
Number of Participants With Any Days for Which the Visitor Felt They Could Communicate With the Patient
Participants for whom their Relative/Partner/Friend (PerLR) felt they could communicate with the participant on at least one day during mechanical ventilation, assessed by the Relative/Partner/Friend (PerLR). It was a binary outcome representing any days for which the visitor felt they could communicate with the patient (yes or no).
Measured: Assessed daily until primary outcome reached, up to 30 days post-randomisation.
Occurance of Anxiety at 180 Days
Anxiety was measured using the anxiety subscale within the Hospital Anxiety and Depression Scale (HADS) questionnaire, measured at 180 days. The range of the score is 0 to 21, with 0 indicating no anxiety symptoms and 21 indicating clinically significant levels of anxiety.
Measured: Measured at 180 days
Occurance of Depression at 180 Days
Depression was measured using the depression subscale within the Hospital Anxiety and Depression Scale (HADS) questionnaire, measured at 180 days. The range of the score is 0 to 21, with 0 indicating no depression symptoms and 21 indicating clinically significant levels of depression.
Measured: Measured at 180 days
Occurance of Post-traumatic Stress at 180 Days
Post-traumatic stress was measured using the Impact of Events Scale - revised (IES-R) questionnaire at 180 days.The Impact of Event Scale - Revised (IES-R) is designed to measure post-traumatic stress disorder (PTSD) symptoms. The range of the score is from 0 to 88. The higher the score, the higher the level of post-traumatic stress at 180 days.
Measured: Measured at 180 days
Cognitive Function Assessment at 180 Days
Cognitive function was measured using the Total number of points on the Montreal Cognitive Assessment Tool telephone version (T-MoCA) questionnaire at 180 days. The higher the score, the greater the cognitive function. The range of the score is from 0 to 22, with 22 indicating high levels of cognitive function.
Measured: Measured at 180 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Aug 2018
- Study start11 Dec 2018
- Primary completion14 Dec 2023
- Study completion31 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Critical IllnessStudies of the same condition, open and under way.
- More trials run by University of EdinburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot
- Masking
- None (open label)
- Enrolment
- 1,404 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Edinburgh
- Sponsor type
- University, hospital or other
- Collaborators
- West Hertfordshire Hospitals NHS Trust, Queen's University, Belfast, The University of Queensland, University Hospital of Wales, Edinburgh Napier University, King's College London, University of Warwick, University of Manchester, Royal Surrey County Hospital NHS Foundation Trust, University College, London, NHS Lothian, Imperial College London, University of Cambridge
- Responsible party
- Sponsor
- Investigators
- Timothy Walsh, MBChB MD MSc, Principal investigator, University of Edinburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03653832
- Sponsor's protocol ID
- AC18022
- Other IDs
- HTA 16/93/01, 2018-001650-98, 243640, 18/SS/0085, 2018
- Acronym
- A2B
- Status last verified
- Jun 2026
- First submitted
- 21 Aug 2018
- Last updated
- 23 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The final trial dataset will be held by the University of Edinburgh on a secure password protected drive. Co-investigators will have the right to access the final data set for the purpose of additional analyses that are consistent with the consent provided by participants. Similarly, any external party can approach the co-investigators to request access to the trial data. In all cases, access to the trial dataset will require approval by a majority of the members of the trial management group and the sponsor (or its delegated representative).
Publications
Emerson LM, Blackwood B, Kydonaki K, McKenzie C, Walsh TS, Aitken LM. The experiences of bedside nurses delivering an intensive care sedation study: A process evaluation within the A2B trial. J Intensive Care Soc. 2025 Nov 6;27(2):145-154. doi: 10.1177/17511437251381951. eCollection 2026 May.
PubMed 41220595Walsh 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.
PubMed 40388916Aitken 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.
PubMed 38580355Walsh 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.
PubMed 38072483
Study at a glance
From the registry record, last updated by the sponsor on 23 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT03653832
- Acronym / sponsor ID
- A2B / AC18022
- Conditions
- Critical Illness
- Keywords
- Sedation, Ventilation
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,404 participants (actual)
- Lead sponsor
- University of EdinburghUniversity, hospital or other
- Collaborators
- West Hertfordshire Hospitals NHS Trust, Queen's University, Belfast, The University of Queensland, University Hospital of Wales, Edinburgh Napier University, King's College London, University of Warwick, University of Manchester, Royal Surrey County Hospital NHS Foundation Trust, University College, London, NHS Lothian, Imperial College London, University of Cambridge
- Study start
- 11 Dec 2018 (actual)
- Primary completion
- 14 Dec 2023 (actual)
- Study completion
- 31 Jul 2024 (actual)
- First posted
- 31 Aug 2018 (actual)
- Results
- Posted 23 Oct 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 patients should be kept less sedated, but it is difficult to get the balance of sedation and comfort right.
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.
Detailed description
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, the investigators 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 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot
| Arm | Type | Receives |
|---|---|---|
| Dexmedetomidine Group | Experimental | Drug: DexmedetomidineFor 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. |
| Clonidine Group | Experimental | Drug: ClonidineFor 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. |
| Usual Care (Propofol) Group | Active comparator | Drug: PropofolUsual 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Patient requiring mechanical ventilation (MV) in an ICU
- Aged 18 or over
- Within 48 hours of first episode of mechanical ventilation in ICU
- Requiring sedation with propofol
- Expected to require a total of 48 hours of MV or more in ICU
Key exclusion criteria (18 listed)
- Acute brain injury (traumatic brain injury; intracranial haemorrhage; ischaemic brain injury from stroke or hypoperfusion)
- Post-cardiac arrest (where there is clinical concern about hypoxic brain injury)
- Status epilepticus
- Continuous therapeutic neuromuscular paralysis at the time of screening or randomisation
- Guillain-Barre Syndrome
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DexmedetomidineAlso: DexdorPatients 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. | Drug | Dexmedetomidine Group |
| ClonidineAlso: CatapresPatients 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. | Drug | Clonidine Group |
| PropofolAlso: DiprivanPatients will continue to receive intravenous propofol according to current usual care. | Drug | Usual Care (Propofol) Group |
Primary outcome
Time to First Successful Extubation Post-randomisation (Hours).
Time frame: Ventilation status will be recorded twice daily from the date of randomisation until the date of documented successful extubation, or 180 days, whichever comes first.
The primary outcome is the time from randomisation to the time of successful extubation (in hours post-randomisation)using an internationally agreed definition
26 secondary outcomes
Mortality
Time frame: The incidence of death as documented in the medical records will be recorded from the date of randomisation until the date of the last follow-up visit at 180 days.
Duration of ICU Stay
Time frame: Time from randomisation until ICU discharge or mortality in ICU
Sedation Quality as Measured by Richmond Agitation and Sedation Scale (RASS)
Time frame: During ICU stay, up to the occurrence of successful extubation, withdrawal, death, or 28 days post-randomisation, whichever occurred first.
Sedation Quality as Measured by Sedation Quality Assessment Tool (SQAT)
Time frame: During ICU stay, up to the occurrence of successful extubation, withdrawal, death, or 7 days post-randomisation, whichever occurred first.
Number of Hours Until First Highest RASS of -2 or Greater
Time frame: During ICU stay, up to the occurrence of successful extubation, withdrawal, death, or 28 days post-randomisation, whichever occurred first.
Number of Days to First Optimum Sedation as Assessed by the Sedation Quality Assessment Tool (SQAT)
Time frame: 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.
Delirium During ICU Stay Within the First 10 Days After Randomisation
Time frame: During ICU stay, in the first 10 days after randomisation
Duration of Delirium During ICU Stay
Time frame: The first 10 days after randomisation during ICU stay
The Number of Patients With Any Pre-specified Drug-related Adverse Events
Time frame: Drug-related adverse events as documented in the medical records were recorded daily from the date of randomisation until the date of documented successful extubation, or 28 days, whichever comes first.
Health - Related Quality of Life - Recalled
Time frame: Measured at 30 days - recall Health - related quality of life prior to ICU admission
Health-related Quality of Life (30 Days)
Time frame: Measured at 30 days
Health-related Quality of Life (90 Days)
Time frame: Measured at 90 days
Health-related Quality of Life (180 Days)
Time frame: Measured at 180 days
Ability to Communicate Pain
Time frame: Measured every 12 hours in ICU until primary endpoint reached, assessed up to 30 days post-randomisation.
Ability to Co-operate With Care
Time frame: Measured every 12 hours in ICU until primary outcome reached, assessed up to 30 days post-randomisation.
Awareness of Surroundings
Time frame: Measured at 90 days
Frightening Experiences
Time frame: Measured at 90 days
Recall of Experiences
Time frame: Measured at 90 days
Satisfaction With Care
Time frame: Measured at 90 days
Number of Participants With Any Days of Wakefulness
Time frame: Assessed daily until primary outcome reached, up to 30 days post-randomisation.
Number of Participants With Any Days Appearing Comfortable to the Visitor
Time frame: Assessed daily until primary outcome reached, up to 30 days post-randomisation.
Number of Participants With Any Days for Which the Visitor Felt They Could Communicate With the Patient
Time frame: Assessed daily until primary outcome reached, up to 30 days post-randomisation.
Occurance of Anxiety at 180 Days
Time frame: Measured at 180 days
Occurance of Depression at 180 Days
Time frame: Measured at 180 days
Occurance of Post-traumatic Stress at 180 Days
Time frame: Measured at 180 days
Cognitive Function Assessment at 180 Days
Time frame: Measured at 180 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41220595Emerson LM, Blackwood B, Kydonaki K, McKenzie C, Walsh TS, Aitken LM. The experiences of bedside nurses delivering an intensive care sedation study: A process evaluation within the A2B trial. J Intensive Care Soc. 2025 Nov 6;27(2):145-154. doi: 10.1177/17511437251381951. eCollection 2026 May.
- Derived from this study: PubMed 40388916Walsh 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.
- Derived from this study: PubMed 38580355Aitken 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.
- Derived from this study: PubMed 38072483Walsh 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.
- Individual participant dataSharing planned: Yes. The final trial dataset will be held by the University of Edinburgh on a secure password protected drive. Co-investigators will have the right to access the final data set for the purpose of additional analyses that are consistent with the consent provided by participants. Similarly, any external party can approach the co-investigators to request access to the trial data. In all cases, access to the trial dataset will require approval by a majority of the members of the trial management group and the sponsor (or its delegated representative).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Timothy Walsh, MBChB MD MSc principal investigator
University of Edinburgh
38 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Dexmedetomidine, Clonidine and Propofol in people with Critical Illness, run by University of Edinburgh at 38 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 38 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to First Successful Extubation Post-randomisation (Hours). (time frame: Ventilation status will be recorded twice daily from the date of randomisation until the date of documented successful extubation, or 180 days, whichever comes first.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03653832, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Oct 2026.