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| ID | Type | Description | Link |
|---|---|---|---|
| HTA 16/93/01 | Other Grant/Funding Number | NIHR HTA Programme | |
| 2018-001650-98 | EudraCT Number | ||
| 243640 | Other Identifier | Integrated Research Application System (IRAS) | |
| 18/SS/0085 | Other Identifier | REC Number |
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| Name | Class |
|---|---|
| West Hertfordshire Hospitals NHS Trust | OTHER |
| Queen's University, Belfast | OTHER |
| The University of Queensland | OTHER |
| University Hospital of Wales |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexmedetomidine | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Time to first successful extubation post-randomisation (hours). | How many hours are participants on the study ventilated for? | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Length of ICU stay | Number of days the participant is in ICU | ICU status will be recorded daily from the date of randomisation until the date of ICU discharge, or 180 days, whichever comes first. |
| Delirium prior to successful extubation |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Timothy Walsh, MBChB MD MSc | University of Edinburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Belfast Health & Social Care Trust | Belfast | United Kingdom | ||||
| South Eastern Health and Social Trust |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41220595 | Derived | 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. | |
| 40388916 | Derived |
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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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| Type | Date | Date Unknown |
|---|---|---|
| Release | Nov 17, 2025 | |
| Reset | Nov 26, 2025 | |
| Release | Jan 6, 2026 |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 25, 2023 | Oct 1, 2024 |
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| 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 |
A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot
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| Clonidine | Drug | 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. |
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| Propofol | Drug | Patients will continue to receive intravenous propofol according to current usual care. |
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Did participants have 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. |
| Duration of Delirium during ICU stay | How many days did participants have delirium during their 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. |
| Sedation quality as measured by Richmond Agitation and Sedation Scale (RASS) | Sedation quality as measured by Richmond Agitation and Sedation Scale (RASS). RASS scale ranges from -5 to +4. optimal score is between -2 and +1. | Sedation quality 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. |
| Sedation quality as measured by Sedation Quality Assessment Tool (SQAT) | Two components of the SQAT assessment will be used in this trial to measure sedation quality. | Sedation quality 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. |
| Analgesia quality as measured by Richmond Agitation and Sedation Scale (RASS) | Quality of Analgesia measured by Richmond Agitation and Sedation Scale (RASS). RASS scale ranges from -5 to +4. optimal score is between -2 and +1. | Analgesia quality 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. |
| Analgesia quality as measured by Sedation Quality Assessment Tool (SQAT) | Quality of Analgesia measured by Sedation Quality Assessment Tool (SQAT) | Analgesia quality 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. |
| Number of hours to first optimum sedation as measured by a RASS score of -2 or greater | 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. |
| 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) | 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. |
| Ability to communicate pain | Binary assessment by bedside nurse | Ability to communicate pain will be assessed twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first. |
| Ability to co-operate with care | Binary assessment by bedside nurse | Ability to co-operate with care will be assessed twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first. |
| Relative/Partner/Friend (PerLR) assessment of wakefulness | PerLR response to verbal question | Participant wakefulness will be 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. |
| Relative/Partner/Friend (PerLR) assessment of patient comfort | PerLR response to verbal question | Comfort of participant will be 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. |
| Relative/Partner/Friend (PerLR) assessment of patient communication | PerLR response to verbal question | Participant communication will be 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. |
| Incidence of Drug-related adverse events - Bradycardia; hypotension; hypertension; cardiac arrhythmias; cardiac arrest | Incidence of drug-related adverse events as documented in the medical records | The incidence of drug-related adverse events as documented in the medical records will be recorded daily from the date of randomisation until the date of documented successful extubation, or 28 days, whichever comes first. |
| Incidence of Mortality | Mortality data collected from medical records | 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. |
| Patient experience of ICU care measured at 90 days | Patient experience of ICU care measured by Intensive Care Experience Questionnaire | 90 days post ICU discharge |
| Occurrence of Anxiety and depression at 180 days | Patient anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) questionnaire | 180 days post ICU discharge |
| Occurrence of Post-traumatic stress at 180 days | Occurence of post-traumatic stress measured by Impact of Events Scale-revised (IES-R) | 180 post ICU discharge |
| Cognitive function assessed at 180 days using the Montreal Cognitive Assessment Tool (Postal or Telephone) | Cognitive function assessed at 180 days using the Montreal Cognitive Assessment Tool (Postal or Telephone) | 180 days post ICU discharge |
| Health related Quality of Life (recalled) assessed by Euroqol tool (EQ-5D-5L) | Health related Quality of Life (recalled) assessed by Euroqol tool (EQ-5D-5L). Scale is between 5-25 which lower scores having the better outcome. | 30 days post ICU discharge - recalled prior to hospital admission |
| Health related Quality of Life (30 day) assessed by Euroqol tool (EQ-5D-5L) | Health related Quality of Life (30 day) assessed by Euroqol tool (EQ-5D-5L). Scale is between 5-25 which lower scores having the better outcome. | 30 days post ICU discharge |
| Health related Quality of Life (90 day) assessed by Euroqol tool (EQ-5D-5L) | Health related Quality of Life (90 day) assessed by Euroqol tool (EQ-5D-5L). Scale is between 5-25 which lower scores having the better outcome. | 90 days post ICU discharge |
| Health related Quality of Life (180 day) assessed by Euroqol tool (EQ-5D-5L) | Health related Quality of Life (180 day) assessed by Euroqol tool (EQ-5D-5L). Scale is between 5-25 which lower scores having the better outcome. | 180 days post ICU discharge |
| 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 |
| 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. |
| 38580355 | Derived | 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. |
| 38072483 | Derived | 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. |
| Unrelease | Jan 14, 2026 |
| Release | Jan 26, 2026 |
| Reset | Feb 9, 2026 |
| Release | Mar 18, 2026 |
| Reset | Apr 7, 2026 |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 27, 2024 | Oct 1, 2024 | SAP_001.pdf |
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| Release Date | Unrelease Date | Unrelease Date Unknown | Reset Date | MCP Release Number |
|---|---|---|---|---|
| Nov 17, 2025 | Nov 26, 2025 | |||
| Jan 6, 2026 | Jan 14, 2026 | |||
| Jan 26, 2026 | Feb 9, 2026 | |||
| Mar 18, 2026 | Apr 7, 2026 | |||
| Jun 18, 2026 |
| ID | Term |
|---|---|
| D016638 | Critical Illness |
| D053120 | Respiratory Aspiration |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| D003000 | Clonidine |
| D015742 | Propofol |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D048288 | Imidazolines |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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