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

Critical Illness Clinical Trial

— A2B  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03653832
• Other study ID #: AC18022
• Secondary ID: HTA 16/93/012018
• Status: Completed
• Phase: Phase 3
• Start date: December 10, 2018
• Est. completion date: December 15, 2023

Study information

• Verified date: May 2024
• Source: University of Edinburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1437
• Est. completion date: December 15, 2023
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Critical Illness

Intervention

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 a2-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 a2-agonist dose is reached or because cardiovascular or other side-effects limit dose escalation.
• Clonidine
Patients will commence intravenous infusion of open-label study drug according to a weight-based dose regimen as early as possible post-randomisation, and within a maximum of two hours. Bedside clinical staff will transition patients to achieve sedation with the allocated a2-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 a2-agonist dose is reached or because cardiovascular or other side-effects limit dose escalation.
• Propofol
Patients will continue to receive intravenous propofol according to current usual care.

Locations

Country	Name	City	State
United Kingdom	Belfast Health & Social Care Trust	Belfast
United Kingdom	South Eastern Health and Social Trust	Belfast
United Kingdom	University Hospitals Birmingham NHS Foundation Trust	Birmingham
United Kingdom	Blackpool Teaching Hospitals NHS Foundation Trust	Blackpool
United Kingdom	North Bristol NHS Trust	Bristol
United Kingdom	University Hospitals Bristol NHS Foundation Trust	Bristol
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Cardiff and Vale University Health Board	Cardiff
United Kingdom	Countess of Chester Hospital NHS Foundation Trust	Chester
United Kingdom	University Hospitals Coventry and Warwickshire NHS Foundation Trust	Coventry
United Kingdom	The Dudley Group NHS Foundation Trust	Dudley
United Kingdom	NHS Dumfries and Galloway	Dumfries
United Kingdom	NHS Lothian	Edinburgh
United Kingdom	Gateshead Health NHS Trust	Gateshead
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	University Hospitals of Morecambe Bay NHS Foundation Trust	Kendal
United Kingdom	The Queen Elizabeth Hospital Kings Lynn NHS Foundation Trust	King's Lynn
United Kingdom	NHS Fife	Kirkcaldy
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	Barking, Haveridge and Redbridge University Hospitals NHS Trust	Romford
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

Sponsors (14)

Lead Sponsor	Collaborator
University of Edinburgh	Edinburgh Napier University, Imperial College London, King's College London, NHS Lothian, Queen's University, Belfast, Royal Surrey County Hospital NHS Foundation Trust, The University of Queensland, University College, London, University Hospital of Wales, University of Cambridge, University of Manchester, University of Warwick, West Hertfordshire Hospitals NHS Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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