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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03653832
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : July 22, 2019
Sponsor:
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
Information provided by (Responsible Party):
University of Edinburgh

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.


Condition or disease Intervention/treatment Phase
Critical Illness Drug: Dexmedetomidine Drug: Clonidine Drug: Propofol Phase 3

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 1737 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.

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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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1737 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
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
Actual Study Start Date : December 10, 2018
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 0.7µg.kg-1.hour-1 titrated to a maximum dose 1.4µg.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 Name: 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 2µg.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 Name: Catapres

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 Name: Diprivan




Primary Outcome Measures :
  1. 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. ]
    How many hours are participants on the study ventilated for?


Secondary Outcome Measures :
  1. Length of ICU stay [ Time Frame: ICU status will be recorded daily from the date of randomisation until the date of ICU discharge, or 180 days, whichever comes first. ]
    Number of days the participant is in ICU

  2. Delirium during ICU stay [ Time Frame: 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. ]
    Did participants have delirium during ICU stay?

  3. Duration of Delirium during ICU stay [ Time Frame: 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. ]
    How many days did participants have delirium during their ICU stay?

  4. Sedation quality as measured by Richmond Agitation and Sedation Scale (RASS) [ Time Frame: 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 Richmond Agitation and Sedation Scale (RASS). RASS scale ranges from -5 to +4. optimal score is between -2 and +1.

  5. Sedation quality as measured by Sedation Quality Assessment Tool (SQAT) [ Time Frame: 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. ]
    Two components of the SQAT assessment will be used in this trial to measure sedation quality.

  6. Analgesia quality as measured by Richmond Agitation and Sedation Scale (RASS) [ Time Frame: 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. ]
    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.

  7. Analgesia quality as measured by Sedation Quality Assessment Tool (SQAT) [ Time Frame: 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. ]
    Quality of Analgesia measured by Sedation Quality Assessment Tool (SQAT)

  8. Number of hours to first optimum sedation as measured by a RASS score of -2 or greater [ Time Frame: 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 hours to first optimum sedation as measured by a RASS score of -2 or greater

  9. 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. ]
    Number of days to first optimum sedation as assessed by the Sedation Quality Assessment Tool (SQAT)

  10. Ability to communicate pain [ Time Frame: 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. ]
    Binary assessment by bedside nurse

  11. Ability to co-operate with care [ Time Frame: 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. ]
    Binary assessment by bedside nurse

  12. Relative/Partner/Friend (PerLR) assessment of wakefulness [ Time Frame: 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. ]
    PerLR response to verbal question

  13. Relative/Partner/Friend (PerLR) assessment of patient comfort [ Time Frame: 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. ]
    PerLR response to verbal question

  14. Relative/Partner/Friend (PerLR) assessment of patient communication [ Time Frame: 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. ]
    PerLR response to verbal question

  15. Incidence of Drug-related adverse events - Bradycardia; hypotension; hypertension; cardiac arrhythmias; cardiac arrest [ Time Frame: 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 drug-related adverse events as documented in the medical records

  16. Incidence of 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. ]
    Mortality data collected from medical records

  17. Patient experience of ICU care, measured at 30 days [ Time Frame: 30 days post ICU discharge ]
    Patient experience of ICU care measured by Intensive Care Experience Questionnaire

  18. Patient experience of ICU care measured at 90 days [ Time Frame: 90 days post ICU discharge ]
    Patient experience of ICU care measured by Intensive Care Experience Questionnaire

  19. Occurrence of Anxiety and depression at 90 days [ Time Frame: 90 days post ICU discharge ]
    Patient anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) questionnaire

  20. Occurrence of Anxiety and depression at 180 days [ Time Frame: 180 days post ICU discharge ]
    Patient anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) questionnaire

  21. Occurrence of Post-traumatic stress at 90 days [ Time Frame: 90 post ICU discharge ]
    Occurence of post-traumatic stress measured by Impact of Events Scale-revised (IES-R)

  22. Occurrence of Post-traumatic stress at 180 days [ Time Frame: 180 post ICU discharge ]
    Occurence of post-traumatic stress measured by Impact of Events Scale-revised (IES-R)

  23. Cognitive function assessed at 90 days using the Montreal Cognitive Assessment Tool (Postal or Telephone) [ Time Frame: 90 days post ICU discharge ]
    Cognitive function assessed at 90 days using the Montreal Cognitive Assessment Tool (Postal or Telephone)

  24. Cognitive function assessed at 180 days using the Montreal Cognitive Assessment Tool (Postal or Telephone) [ Time Frame: 180 days post ICU discharge ]
    Cognitive function assessed at 180 days using the Montreal Cognitive Assessment Tool (Postal or Telephone)

  25. Health related Quality of Life (recalled) assessed by Euroqol tool (EQ-5D-5L) [ Time Frame: 30 days post ICU discharge - recalled prior to hospital admission ]
    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.

  26. Health related Quality of Life (30 day) assessed by Euroqol tool (EQ-5D-5L) [ Time Frame: 30 days post ICU discharge ]
    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.

  27. Health related Quality of Life (90 day) assessed by Euroqol tool (EQ-5D-5L) [ Time Frame: 90 days post ICU discharge ]
    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.

  28. Health related Quality of Life (180 day) assessed by Euroqol tool (EQ-5D-5L) [ Time Frame: 180 days post ICU discharge ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient requiring mechanical ventilation (MV) in an ICU
  2. Aged 18 or over
  3. Within 48 hours of starting MV in an 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03653832


Contacts
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Contact: Timothy Walsh, MBChB MD MSc +44 1312423137 timothy.walsh@ed.ac.uk
Contact: Julia A Boyd, PhD +44 1316519908 julia.boyd@ed.ac.uk

Locations
Show Show 18 study locations
Sponsors and Collaborators
University of Edinburgh
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
Investigators
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Principal Investigator: Timothy Walsh, MBChB MD MSc University of Edinburgh

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Responsible Party: University of Edinburgh
ClinicalTrials.gov Identifier: NCT03653832    
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 )
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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).
Supporting Materials: Study Protocol
Time Frame: Currently unknown
Access Criteria: Currently unspecified

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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
Keywords provided by University of Edinburgh:
Sedation
Ventilation
Additional relevant MeSH terms:
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Critical Illness
Disease Attributes
Pathologic Processes
Clonidine
Dexmedetomidine
Propofol
Adrenergic alpha-2 Receptor Agonists
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Sympatholytics
Autonomic Agents