A Phase III, Multi-Arm Multi-Stage Covariate-Adjusted Response-Adaptive Randomised Trial to Determine Optimal Early Mobility Training after Stroke (AVERT DOSE).

RationaleThe evidence base for acute post-stroke rehabilitation is inadequate and global guideline recommendations vary.AimTo define optimal early mobility intervention regimens for ischaemic stroke patients of mild and moderate severity.HypothesesCompared to a pre-specified reference arm, the optimal dose regimen(s) will result in: more participants experiencing little or no disability (mRS 0-2) at 3 months post stroke (primary), fewer deaths at 3 months, fewer and less severe complications during the intervention period, faster recovery of unassisted walking and better quality of life at 3 months (secondary). We also hypothesise these regimens will be more cost-effective.Sample size estimatesFor the primary outcome, recruitment of 1300 mild and 1400 moderate participants will yield 80% power to detect a 10% risk difference.Methods and designMulti-Arm Multi-Stage Covariate-Adjusted Response-Adaptive randomised trial of mobility training commenced within 48 hours of stroke in mild (NIHSS<7) and moderate (NIHSS 8-16) stroke patient strata, with analysis of blinded outcomes at 3 (primary) and 6 months. Eligibility criteria are broad, while excluding those with severe premorbid disability (mRS >2) and haemorrhagic stroke. With four arms per stratum (reference arm retained throughout), only the single treatment arm demonstrating the highest proportion of favourable outcomes at the first stage will proceed to second stage in each stratum, resulting in a final comparison with the reference arm. Three prognostic covariates of age, geographic region and reperfusion interventions, as well as previously observed mRS0-2 responses inform the adaptive randomisation procedure. Participants randomised receive prespecified mobility training regimens (functional task-specific), provided by physiotherapists/nurses until discharge or 14 days. Interventions replace usual mobility training.Fifty hospitals in seven countries (Australia, Malaysia, United Kingdom, Ireland, India, Brazil, Singapore) are expected to participate.SummaryOur novel adaptive trial design will evaluate a wider variety of mobility regimes than a traditional two arm design. The data-driven adaptions during the trial will enable a more efficient evaluation to determine the optimal early mobility intervention for patients with mild and moderate ischaemic stroke.