Clinical trial NCT03653832: Alpha 2 Agonists for Sedation to Produce Better Outcomes From Critical Illness (A2B Trial)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Critical Illness
Keywords: Sedation
Ventilation
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: West Hertfordshire Hospitals NHS Trust
name: Queen's University, Belfast
name: The University of Queensland
name: University Hospital of Wales
name: Edinburgh Napier University
name: King's College London
name: University of Warwick
name: University of Manchester
name: Royal Surrey County Hospital NHS Foundation Trust
name: University College, London
name: NHS Lothian
name: Imperial College London
name: University of Cambridge
First posted: 2018-08-31
Enrollment: 1437
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to first successful extubation post-randomisation (hours).
timeFrame: 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:
measure: Length of ICU stay
timeFrame: ICU status will be recorded daily from the date of randomisation until the date of ICU discharge, or 180 days, whichever comes first.
measure: Delirium prior to successful extubation
timeFrame: 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.
measure: Duration of Delirium during ICU stay
timeFrame: 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.
measure: Sedation quality as measured by Richmond Agitation and Sedation Scale (RASS)
timeFrame: 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.
measure: Sedation quality as measured by Sedation Quality Assessment Tool (SQAT)
timeFrame: 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.
measure: Analgesia quality as measured by Richmond Agitation and Sedation Scale (RASS)
timeFrame: 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.
measure: Analgesia quality as measured by Sedation Quality Assessment Tool (SQAT)
timeFrame: 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.
measure: Number of hours to first optimum sedation as measured by a RASS score of -2 or greater
timeFrame: 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.
measure: Number of days to first optimum sedation as assessed by the Sedation Quality Assessment Tool (SQAT)
timeFrame: 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.
measure: Ability to communicate pain
timeFrame: 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.
measure: Ability to co-operate with care
timeFrame: 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.
measure: Relative/Partner/Friend (PerLR) assessment of wakefulness
timeFrame: 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.
measure: Relative/Partner/Friend (PerLR) assessment of patient comfort
timeFrame: 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.
measure: Relative/Partner/Friend (PerLR) assessment of patient communication
timeFrame: 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.
measure: Incidence of Drug-related adverse events - Bradycardia; hypotension; hypertension; cardiac arrhythmias; cardiac arrest
timeFrame: 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.
measure: Incidence of Mortality
timeFrame: 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.
measure: Patient experience of ICU care measured at 90 days
timeFrame: 90 days post ICU discharge
measure: Occurrence of Anxiety and depression at 180 days
timeFrame: 180 days post ICU discharge
measure: Occurrence of Post-traumatic stress at 180 days
timeFrame: 180 post ICU discharge
measure: Cognitive function assessed at 180 days using the Montreal Cognitive Assessment Tool (Postal or Telephone)
timeFrame: 180 days post ICU discharge
measure: Health related Quality of Life (recalled) assessed by Euroqol tool (EQ-5D-5L)
timeFrame: 30 days post ICU discharge - recalled prior to hospital admission
measure: Health related Quality of Life (30 day) assessed by Euroqol tool (EQ-5D-5L)
timeFrame: 30 days post ICU discharge
measure: Health related Quality of Life (90 day) assessed by Euroqol tool (EQ-5D-5L)
timeFrame: 90 days post ICU discharge
measure: Health related Quality of Life (180 day) assessed by Euroqol tool (EQ-5D-5L)
timeFrame: 180 days post ICU discharge
Other outcomes:
Locations:
city: Belfast
country: United Kingdom
facility: Belfast Health & Social Care Trust
city: Belfast
country: United Kingdom
facility: South Eastern Health and Social Trust
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Blackpool
country: United Kingdom
facility: Blackpool Teaching Hospitals NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: North Bristol NHS Trust
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale University Health Board
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital NHS Foundation Trust
city: Dudley
country: United Kingdom
facility: The Dudley Group NHS Foundation Trust
city: Dumfries
country: United Kingdom
facility: NHS Dumfries and Galloway
city: Edinburgh
country: United Kingdom
facility: NHS Lothian
city: Gillingham
country: United Kingdom
facility: Medway NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
city: Harrogate
country: United Kingdom
facility: Harrogate and District NHS Trust
city: Hereford
country: United Kingdom
facility: Wye Valley NHS Trust
city: King's Lynn
country: United Kingdom
facility: The Queen Elizabeth Hospital Kings Lynn NHS Foundation Trust
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester
city: Lewisham
country: United Kingdom
facility: Lewisham and Greenwich NHS Trust
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital Foundation Trust
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen University Hospitals NHS Trust
city: London
country: United Kingdom
facility: Guys and St Thomas NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester University Foundation Trust
city: Newcastle
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals NHS Foundation Trust
city: Newport
country: United Kingdom
facility: Aneurin Bevan University Health Board
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust.
city: Poole
country: United Kingdom
facility: Poole Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHSFT
city: Stockton-on-Tees
country: United Kingdom
facility: North Tees and Hartlepool NHS Foundation Trust
city: Taunton
country: United Kingdom
facility: Taunton and Somerset NHS Foundation Trust
city: Watford
country: United Kingdom
facility: West Hertfordshire Hospitals NHS Trust
Study officials:
affiliation: University of Edinburgh
name: Timothy Walsh, MBChB MD MSc
role: PRINCIPAL_INVESTIGATOR
References: