Jacqueline Ancliffe MCSP, MSc, FACP A Very Early Rehabilitation Trial (AVERT): Primary outcome at 3 months post stroke Jacqueline Ancliffe MCSP, MSc, FACP on behalf of The AVERT Trial Collaboration group The AVERT Trial Collaboration Group. 56 hospitals in five countries. Australia, New Zealand, Singapore, Malaysia, United Kingdom

AVERT: A pragmatic, ‘real world’ trial Design International, multicentre, parallel group, randomised controlled trial testing efficacy and safety of a very early (<24h) frequent, higher dose out of bed (very early mobilisation) protocol compared to usual care post stroke. Protocol Bernhardt IJS 2006; Bernhardt IJS 2015 SAP

Clinical hypotheses Early rehab delivered by a PT/nurse team will: Improve functional outcome (mRS 0-2) at 3 months Lead to fewer immobility complications at 3 months post stroke Lead to more patients regaining the ability to walk early Results in better quality of life at 12 months Be cost effective 12 month outcomes Bernhardt et al 2015 The Lancet

Eligibility Inclusion criteria Exclusion criteria TIA Confirmed stroke (first / recurrent, IS/ICH) Less than 24 hrs symptom onset Age > 18 years, no upper limit Physiological parameters within set limits: Systolic BP 110-220 mmHG; O2 sats > 92%; HR 40-110; temp < 38.2o; rouseable to voice rtPA permitted Inclusion criteria TIA Mod – severe premorbid disability Admitted directly to ICU Unstable cardiac conditions, severe heart failure Progressive neurological conditions For palliative care Exclusion criteria

3+additional out of bed sessions/day Trial pathway Sample size, n=2104 3+additional out of bed sessions/day Very Early Mobilisation + Usual Care Arrive hospital, screened, recruited < 24 hrs First intervention, < 24 hrs PT /Nurse team, 6 days/wk Day 14 Treatment ceases 3 month Ax 1o outcome 12 month Ax Stroke Stratified by stroke severity & site 1o Efficacy endpoint Favourable outcome (mRS 0-2) Safety outcomes: death, SAEs, immobility, neurological Usual care until discharge Critical elements of VEM protocol: commenced within 24 hours focus on ‘out of bed’ mobilisation activities, and provided at least three additional (to UC) out of bed sessions per day Continued for 14 days or until discharge from stroke unit care Visit by blinded assessor or telephone to assess: mRS SAEs Barthel Index Rivermead Irritability, depression and anxiety (IDA) scale Assessment of Quality of Life (AQoL) Montreal Cognitive Assessment (MoCA) Comprehensive cost questionnaire

Methods: Key analyses Efficacy Safety Primary: Favourable outcome mRS 0-2 Secondary: Assumption free ordinal shift analysis Time to walking unassisted 50 metres Exploratory: Subgroups – age (<65; 65–79; >80), stroke severity (mild: NIHSS<7; moderate: 8–16; and severe: >16), stroke type (infarct, haemorrhage), rtPA, time to first mobilisation (<12 h; 12–24 h; >24 h) Safety Death at 3 months Serious adverse events with separate review of immobility-related, neurological Dose of intervention (time to start, frequency, amount) Change in dose over time Adjusted for age and baseline NIHSS Bernhardt IJS 2015 Statistical Analysis Plan

Follow up complete in 2083 patients Trial Performance 25,237 admitted <24 hours of stroke onset 1054 very early mobilisation 23,133 ineligible 5588 premorbid mRS>2 1136 other clinical trial 7080 medically unstable/unwell 7414 no recruiter/weekend 8151 other exclusion reason 446 refused 2104 enrolled 12 never mobilised 21 not stroke 2104 randomised 1050 usual care 14 never mobilised 13 not stroke 1038 assessed at 3 months 950 alive 88 dead 6 unknown 10 refused follow up 1045 assessed at 3 months 973 alive 72 dead 5 refused follow up 1054 included in intention-to-treat primary analysis 1050 included in intention-to-treat primary analysis July 06 – October 14 56 sites 5 countries: Australia New Zealand Malaysia Singapore UK Follow up complete in 2083 patients (99%) Figure 1: Trial profile

Baseline characteristics VEM (n=1054) Usual care (n=1050) Recruitment region   Australia/New Zealand 617 (59%) 626 (60%) Asia 126 (12%) 125 (12%) UK 311 (29%) 299 (28%) Patient Details Age (Median, IQR) 72·3 (62·3, 80·3) 72·7 (63·4, 80·4) Female 411 (39%) 407 (39%) Risk Factors Hypertension 707 (67%) 717 (68%) Ischaemic Heart Disease 235 (22%) 251 (24%) Hypercholesterolaemia 419 (40%) 423 (40%) Diabetes mellitus 239 (23%) 228 (21%) Smoker 227 (22%) 204 (19%) Atrial Fibrillation 229 (22%) 237 (23%) Premorbid history Living at home at time of admission 1038 (99%) 1036 (99%) Time to randomisation (hours) Median (IQR) 18·2 (12·1–21·8) 18·2 (12·5–21·8) Stroke history First Stroke 878 (83%) 843 (80%) NIHSS Score, Median (IQR)  7 (4–12) 7 (4–12) Mild (1–7) 592 (56%) 578 (55%) Moderate (8–16) 315 (30%) 328 (31%) Severe (> 16) 147 (14%) 144 (14%) Stroke type (Oxfordshire Classification) TACI 224 (21%) 232 (22%) PACI 340 (32%) POCI 93 (9%) 106 (10%) LACI 255 (24%) 268 (26%) ICH 142 (14%) 116 (11%) rtPA treatment 247 (23%)   260 (25%) Baseline characteristics 26% patients over age of 80 years 45% patients mod-severe stroke (NIHSS>7) 31% <65years, premorbid mRS 1 or 2 (VEM 24%; US 25%) 86% walking independently witout aide VEM, 88% UC 24% rtPA

Intervention achieved significant differences Time reduced by 28mins/year 95% CI 11·3–44·6, p=0·001 VEM Usual Care median, IQR n=1054 n=1050 p value median shift (95% CI) Time to first mobilisation (hrs) 18·5 (12·8–22·3) 22·4 (16·5–29·3) <0·0001 4·8 (4·1–5·7) n=1042; missing*=12 n=1036; missing*=14   Frequency per person (median daily sessions of out of bed activity) 6·5 (4·0–9·5) 3 (2·0–4·5) 3 (3–3·5) Daily amount per person* (median minutes per day spent in out of bed activity) 31 (16·5–50·5) 10 (0–18) 21·0 (20–22·5) Total amount per person (mins over the intervention period) 201·5 (108–340) 70 (32–130) 117 (107–128) 75% of all patients started out of bed activity <24 hours 85,000 episodes of care recorded NOT sitting out of bed * Minutes derived from physiotherapy data only

Favourable outcome (mRS 0-2) 480, 46% OR 0.73, 95% CI 0.59–0.90, p=0.004 525, 50%

Favourable outcome (mRS 0-2) Assumption free ordinal analysis (GenOR 0.94, 95% CI 0.85–1.03, p=0.193)

Time to walking 50 metres unassisted Days post stroke Number of patients who had not achieved walking Proportion walking 50m unassisted VEM Usual care HR 1.04 95%CI0.94-1.15, p=0.459

Outcome by subgroup (mRS 0-2) n OR Favours Usual care Favours VEM Outcome by subgroup (mRS 0-2) No significant treatment by group interactions p>0.05 None of the individual subgroup analyses revealed a significant treatment by subgroup interaction: p>0.05

(Adjusted baseline NIHSS, age) Safety VEM Usual Care Analysis   n (%) (Adjusted baseline NIHSS, age) N=1048 N=1050 OR (95% CI) p value Death 88 (8·4%) 72 (6·9%) 1·34 (0·93–1·93) 0·113 Non-fatal SAEs IRR (95% CI) None 853 (80·9%) 842 (80·2%) 0·88 (0·72–1·07) 0·194 1 157 (14·9%) 146 (13·9%) 2 32 (3·0%) 41 (3·9%) 3 10 (1·0%) 16 (1·5%) 4 2 (0·2%) 4 (0·4%) 5 0 (0%) 1 (0·1%) Immobility SAEs 1000 (94·9%) 997 (95·0%) 0·92 (0·62–1·35) 0·665 50 (4·7%) 46 (4·4%) 5 (0·5%) ≥4 Neurological SAEs 947 (89·9%) 967 (92·1%) 1·26 (0·95–1·66) 0·108 104 (9·9%) 78 (7·4%) 3 (0·3%) Main causes of death (64% of total) VEM UC Stroke progression 31 19 Pneumonia 19 15 Recurrent stroke 11 7 Analyses are adjusted for age and baseline NIHSS

Conclusions (1) 1. Meeting protocol is a key challenge in rehabilitation trials We achieved a significant difference in the frequency, amount and timing of rehabilitation 2. The very early, higher dose out of bed activity protocol reduced the odds of favourable outcome, without accelerating walking recovery or reducing immobility-related SAEs ‘more is better’ may not apply in the first few days after stroke 3. There were low rates of death or serious adverse events, with non-significant differences that suggests signals of harm in ICH and severe stroke Treatment dose versus benefits/harms warrants further exploration

Conclusions (2) The high quality data in this international trial provides the best opportunity yet to determine the best pattern of rehabilitation. The interventions delivered in this trial are ‘complex’. We have shown the world that these trials are feasible Further exploration will help underpin clinical practice guidelines Understanding the components that lead to benefit or harm is a priority, pre-specified dose-response analyses important

AVERT Collaboration

AVERT Royal Perth Hospital Team

AVERT (a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to staff Absences owing to parental leave led to delayed recruitment and increased costs Implications for future trials http://www.bmj.com/content/351/bmj.h6432.full

Further acknowledgements: Volunteer committees: Steering Committee, Data Safety and Monitoring Committee, Outcomes Committee Funding: The National Health and Medical Research Council (NHMRC) of Australia. Chest Heart and Stroke Scotland, Northern Ireland Chest Heart and Stroke, Singapore Health, The Stroke Association, UK, the National Institute of Health Research, UK