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

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. 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. 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. 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. 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. Costs and Outcomes: The primary outcome is time to successful extubation (in hours post-randomisation) using an internationally agreed definition. 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. 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. Health Economic evaluation: We will compare costs and assess within-trial and lifetime cost-effectiveness from an NHS and PSS perspective. 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. Follow up: Up to 6 months post-randomisation. 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. 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. 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.