Award 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
Funder: Chief Scientist Office, Scotland

Abstract: 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, we want to keep patients less sedated, but it is difficult to get the balance of sedation and comfort right. _x000D_
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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 ('dex'). _x000D_
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We 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 with these drugs. We also want to know how safe they are and if they can improve important outcomes during ICU stay (like delirium, comfort, and safety) and during recovery (like bad memories, anxiety, and depression). We also want to know if they are value for money._x000D_
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Our trial will include 1737 patients needing to be on a ventilator for at least 2 days. Patients will be allocated to one of three groups by chance. One group will receive propofol; one group will receive dexmedetomidine; and one group will receive clonidine. All patients will receive extra pain relief if needed. Nurses and doctors will alter the doses of sedation drugs to try and reduce or stop them, but always aiming to have patients lightly sedated and comfortable. We will compare if patients on dexmedetomidine or clonidine come off the ventilator quicker than those just on propofol. We will also see if there was a difference between the groups in the number of people who experienced delirium in ICU, compare how comfortable people were, and measure if participants memories of being in the ICU differed. _x000D_
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Patients who were in the trial will be followed up for 180 days afterwards because we want to compare if there were differences in the after-effects of being ill in ICU between the groups. We will ask patients 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, we will also ask patients to complete questionnaires so that we can detect how they feel about their quality of life or if they suffer from anxiety, depression or stress._x000D_
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Alongside this trial, we 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. We will also find out ICU nurses’ and doctors’ views on how easy or difficult it was to adjust and use the drugs. This will give us 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. _x000D_
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We have a large experienced team of people guiding this study. They include doctors, nurses, pharmacists, health economists, statisticians, ex-patients and others who have expertise in the study methods. Together they will ensure that the trial runs smoothly, safely and finishes on time.

Lay Abstract: Design: A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot. Patients will be randomised via a web-based system to one of the intervention groups or a ‘usual care’ control arm in a 1:1:1 ratio._x000D_
Setting: 40-50 Intensive Care Units (ICUs) within NHS hospitals with a patient case mix typical of UK critical care, selected from an established network with a proven track record of successful participation in clinical trials._x000D_
Population: Adult ICU patients within 48 hours of starting mechanical ventilation (MV), expected to require at least 24 hours further MV at randomisation. Exclusions include patients with primary brain injury; post-cardiac arrest; status epilepticus; and peripheral nervous system disease._x000D_
Health technologies being assessed: Alpha2-agonist drugs (either clonidine or dexmedetomidine) by continuous infusion to provide sedation after intubation and initial stabilisation, in combination with opioid drugs as required. For all patients the target will be an awake comfortable patient within the shortest safe time-scale. Weaning from MV will follow current guidelines for frequent reduction in MV support._x000D_
Control group treatment: Continuation of drugs used for intubation and stabilisation on MV (propofol and opioid) by continuous infusion. Sedation targets and weaning procedures will be the same as for the intervention groups._x000D_
Costs and Outcomes: The primary outcome is time to successful extubation (in hours post-randomisation) using an internationally agreed definition. _x000D_
Secondary outcomes in ICU comprise: delirium, time to optimum sedation, mortality, overall sedation quality, ability to communicate with staff, ICU length of stay, pre-defined drug related adverse events. Secondary outcomes during 6 month follow-up comprise: mortality, patients’ recalled experience of ICU stay, anxiety and depression, post-traumatic stress, cognitive function, health-related quality of life._x000D_
The minimum clinically important difference is a mean of 2 days MV. Analyses will compare outcomes for both alpha2-agonist groups with usual care, and also explore the relative clinical and cost effectiveness of the two interventions._x000D_
Health Economic evaluation: We will compare costs and assess within-trial and lifetime cost-effectiveness from an NHS and PSS perspective._x000D_
Process evaluation: We will explore the processes involved in delivering the intervention to identify factors and the mechanisms of their interaction likely impacting on trial outcomes._x000D_
Follow up: Up to 6 months post-randomisation._x000D_
Sample size: 579 per group (1737 in total). Allows 5% drop out or loss to follow-up prior to primary outcome. Sample size is based on simulations using UK patient data from a recent sedation trial._x000D_
Project time frames: After a 3 month set-up period, the internal pilot will run for 6 months. On reaching the pre-defined recruitment milestones, the internal pilot will run seamlessly into the main trial. We will accrue our target sample size in a further 46 months and follow up for 6 months. Analysis will require a further 6 months. Therefore the total project duration is 66 months._x000D_
Expertise: Our team includes intensivists, nurses, pharmacists, geriatrician, trialists, statisticians, a health economist, and PPI applicant. Expertise in ICU trial design/management, sedation trials, delirium, decision-making, process evaluation, ICU outcomes, and economic evaluations.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: GENERIC HEALTH RELEVANCE