Title: A very early rehabilitation trial after stroke (AVERT): A phase 3 multicentre randomised controlled trial
Funder: Chief Scientist Office (Scotland)

Abstract: AVERT is a large phase III multicentre single-blind controlled parallel group trial with equal randomisation and blinded assessment of outcomes in acute stroke patients (within 24 hours of onset) who are admitted to a stroke unit. Participants are randomised to receive very early mobilisation plus usual care or usual care alone. An international multicentre design was chosen so that participants could be recruited from a wider population and the AVERT intervention could be tested in a range of clinical settings. The consequence is an experimental environment which is more relevant to future use.• Health technologies being assessed: The health technology being assessed is very early mobilisation (VEM); focused task specific mobility training (eg. sitting out of bed standing and walking) commenced within 24 h post-stroke. This is compared to usual stroke unit care. VEM treatment: Patients are assisted by trained nurses or therapists to get out of bed standing and walking whenever possible. This starts < 24 hours after stroke and continues frequently and daily for up to 14 days (or until discharge whatever occurs first). Stroke severity and functional capacity (measured using the Mobility Scale for Acute Stroke) dictate which of the four intervention Levels (1-4) applies. Doses range from 4 times a day (Level 1 for severe stroke fully dependent) to 16 times a day (Level 4 for mild stroke little or no functional dependence).• Measurement of costs and outcomes:Regulatory authorities recommend functional assessment scales for outcome assessment in stroke trials. The primary outcome of this study is the proportion of patients dead or disabled (Modified Rankin Scale (mRS) score 3-5) at 3 months post stroke. The use of the mRS enables categorisation of patients based on six levels of ordered dependency and the ability to look after themselves in daily life with 0-2 representing mild or no disability (good outcome) and 3-5 representing moderate to severe disability (poor outcome). The Modified Rankin scale is the most commonly used functional measure in contemporary stroke trials(16).An economic evaluation will be undertaken alongside the clinical trial from the perspective of the UK NHS and personal social services. In addition to the clinical data resource use data will be collected during the trial; unit costs will be obtained from routinely collected data and literature. Health utility values will be estimated using an algorithm to translate the modified Rankin scale (mRS) into EQ-5D utility values. Cost-effectiveness will be expressed as incremental cost per quality adjusted life year gained. Appropriate sensitivity analyses including probabilistic sensitivity analysis will also be carried out.The global target recruitment is 2104 by late 2014. By September 2012 1363 participants were enrolled in AVERT globally (253 from the UK 269 from New Zealand and SE Asia 841 from Australia). Based on UK recruitment rates in 2012 we anticipated having recruited at least 300 stroke patients from UK hospital sites by the present time (we had recruited 319 by 18.01.13). We plan to expand the number of UK recruitment sites (from 23 to 34) and increase the UK recruitment rate from the current 13 participants per month to 15 per month between February 2013 and October 2014 meaning that by the end of the trial the UK would have contributed a further 330 participants (final UK total 630; 30% of all AVERT participants).The last patient enrolled will have their 90 day follow-up in January 2015. The database will then be locked and analyses for 90 day outcomes carried out. We intend that the primary analyses and main outcomes will be presented at the European Stroke Conference in May 2015 with fast track publication of the results in The Lancet to coincide with this meeting. The AVERT protocol has been reviewed and approved by The Lancet which guarantees fast track publication.The trial will officially end once all 12 month follow ups are completed. The proposed timescale depends on increasing local recruitment site conditions ethics approval and the agreement of funding bodies and therefore more trial manager support will be required to manage and monitor the trial in the UK.• Setting: State the health service setting(s) in which the study will occur: Hospital based stroke units in NHS hospitals.• Target Population: Define the population from which the study sample will be recruited Inclusion criteria: • age 18 years and over• clinical diagnosis of first or recurrent stroke (haemorrhage or infarct) and presenting to hospital within 24 hr of onset of stroke symptoms• admitted to a stroke unit.• Consciousness: at a minimum patient must at least react to verbal commands. Patients who have received alteplase can be recruited if the attending physician permits mobilisation within 24 hours.Exclusion criteria:• significant premorbid disability (modified Rankin scale >2)• if patient is too ill (early significant deterioration admission to intensive care unstable coronary condition (e.g. acute myocardial infarction or other medical condition that is judged by the investigator to impose a hazard to the patient should they be involved in the trial)• if patient’s physiological variables (blood pressure oxygen heart rate temperature) fall outside set safety limits.• Sample sizeThe study is powered to detect an absolute risk reduction of death and disability of 7.1% or greater based on the following rationale: consensus among investigators and international advisors that an absolute risk reduction of this magnitude would represent a clinically meaningful effect size (although there are no formal cost-effectiveness data to support this view); and 3-month death and institutionalisation figures from hospitalised patients from the Australian stroke incidence study NEMESIS (40.9%) and one of the few very early mobilisation centres in Norway (31.8%) and estimates that very early mobilization accounts for 78% of this 9.1% difference giving a final absolute difference of 7.1%. A sample of 2104 patients (1052 per arm) will provide 80% power to detect a significant intervention effect (2-sided p=0.05) with adjustments for a 5% drop-in and a 10% drop-out. A recent meta-analysis of 2 pilot studies (103 participants) supports these power calculations.


Research activity codes: 6.7 PHYSICAL
Health categories: STROKE