Alpha 2 Agonists for Sedation to Produce Better Outcomes From Critical Illness (A2B Trial) (A2B)

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.

Study Overview

• Status: Completed
• Conditions: Critical Illness
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Clonidine; Drug: Propofol

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 Type: Interventional
• Enrollment (Actual): 1437
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Belfast, United Kingdom
    • Belfast Health & Social Care Trust
  • Belfast, United Kingdom
    • South Eastern Health and Social Trust
  • Birmingham, United Kingdom
    • University Hospitals Birmingham NHS Foundation Trust
  • Blackpool, United Kingdom
    • Blackpool Teaching Hospitals NHS Foundation Trust
  • Bristol, United Kingdom
    • University Hospitals Bristol NHS Foundation Trust
  • Bristol, United Kingdom
    • North Bristol NHS Trust
  • Cambridge, United Kingdom
    • Cambridge University Hospitals NHS Foundation Trust
  • Cardiff, United Kingdom
    • Cardiff and Vale University Health Board
  • Chester, United Kingdom
    • COUNTESS OF CHESTER HOSPITAL NHS FOUNDATION TRUST
  • Dudley, United Kingdom
    • The Dudley Group NHS Foundation Trust
  • Dumfries, United Kingdom
    • NHS Dumfries and Galloway
  • Edinburgh, United Kingdom
    • NHS Lothian
  • Gillingham, United Kingdom
    • Medway NHS Foundation Trust
  • Glasgow, United Kingdom
    • NHS Greater Glasgow and Clyde
  • Harrogate, United Kingdom
    • Harrogate and District NHS Trust
  • Hereford, United Kingdom
    • Wye Valley NHS Trust
  • King's Lynn, United Kingdom
    • The Queen Elizabeth Hospital Kings Lynn NHS Foundation Trust
  • Leeds, United Kingdom
    • Leeds Teaching Hospitals NHS Trust
  • Leicester, United Kingdom
    • University Hospitals of Leicester
  • Lewisham, United Kingdom
    • Lewisham and Greenwich NHS Trust
  • Liverpool, United Kingdom
    • Royal Liverpool and Broadgreen University Hospitals NHS Trust
  • Liverpool, United Kingdom
    • Aintree University Hospital Foundation Trust
  • London, United Kingdom
    • University College London Hospitals 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
    • Guys and St Thomas NHS Foundation Trust
  • Manchester, United Kingdom
    • Manchester University Foundation Trust
  • Newcastle, United Kingdom
    • The Newcastle Upon Tyne Hospitals NHS Foundation Trust
  • Newport, United Kingdom
    • Aneurin Bevan University Health Board
  • Nottingham, United Kingdom
    • Nottingham University Hospitals NHS Trust
  • Oxford, United Kingdom
    • Oxford University Hospitals NHS Foundation Trust.
  • Poole, United Kingdom
    • Poole Hospitals NHS Foundation Trust
  • Southampton, United Kingdom
    • University Hospital Southampton NHSFT
  • Stockton-on-Tees, United Kingdom
    • North Tees and Hartlepool NHS Foundation Trust
  • Taunton, United Kingdom
    • Taunton and Somerset NHS Foundation Trust
  • Watford, United Kingdom
    • West Hertfordshire Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient requiring mechanical ventilation (MV) in an ICU
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:

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
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Propofol; Patients will continue to receive intravenous propofol according to current usual care.; Other Names: Diprivan
Experimental: 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.	Drug: 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.; Other Names: Dexdor
Experimental: 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.	Drug: 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.; Other Names: Catapres

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: King's College London; Imperial College London; University College, London; Queen's University, Belfast; NHS Lothian; University of Cambridge; University of Manchester; University of Warwick; Edinburgh Napier University; The University of Queensland; University Hospital of Wales; Royal Surrey County Hospital NHS Foundation Trust; West Hertfordshire Hospitals NHS Trust
• Investigators: Principal Investigator: Timothy Walsh, MBChB MD MSc, University of Edinburgh

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2018
• Primary Completion (Actual): December 14, 2023
• Study Completion (Actual): July 31, 2024

Study Registration Dates

• First Submitted: August 21, 2018
• First Submitted That Met QC Criteria: August 28, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 1, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Sedation; Ventilation
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Sympatholytics; Propofol; Dexmedetomidine; Clonidine
• Other Study ID Numbers: AC18022; 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)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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).
• IPD Sharing Time Frame: Currently unknown
• IPD Sharing Access Criteria: Currently unspecified
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No