A Phase 3, Multi-Arm Multi-Stage Covariate-Adjusted Response-Adaptive Randomised Trial to Determine Optimal Early Mobility Training after Stroke (AVERT DOSE)

Aims

The aim of this study is to define the optimal early intervention regimens that provide the most benefit for people with the ischaemic stroke of mild and moderate severity.

Hypothesis

We hypothesise that against a pre-specified control, the optimal dose intervention regimen(s) will result in:

1. More patients experiencing no or little disability at 3 months post-stroke, (primary outcome)

2. Patients experiencing fewer and less severe complications at 14 days

3. Better quality of life at 6 months and

4. More cost-effective care at 6 months

Method

We will use a multi-arm, dose-finding, Covariate-Adjusted, Response-Adaptive (CARA) Randomised Clinical Trial in two specified mild and moderate stroke severity strata.

We will test three separate rehabilitation intervention regimens in each strata against a pre-specified control to identify the intervention regimen that results in fewer disabled patients at 3 months post-stroke (mRS 0-2). A sample size of 2,572 patients will allow us to independently observe pre-specified effects in these two strata with power 80% and significance threshold of p=0.025. All analyses will be intention-to-treat. Patients with mild to moderate stroke will be recruited using our global trials network in Australia, New Zealand, Singapore, Malaysia, India and the United Kingdom as well as additional interested collaborators.

Number of participants

2,572 stroke patients will be recruited, with 1470 mild severity (National Institute of Health Stroke Scale (NIHSS),15 0-7) and 1102 moderate severity (NIHSS 8-16).

Stroke Unit Care

Hospitals with a geographically located stroke unit are selected for this study.

Inclusion Criteria

• Ischaemic stroke (first-ever or recurrent)

• Aged ≥ 18 years

• Ability to be enrolled within 48 hours of the onset of stroke symptoms.

• Mild (NIHSS 0-7) to moderate stroke severity (NIHSS 8 -16),

• Pre stroke mRS of 0 – 2

• Meet physiological criteria indicating a stable medical condition (patient rousable, with systolic BP > 120 mmHg and < 180 mmHg, O2 saturation > 92%, HR > 40 and < 100, and temperature < 38.5ºC).

Exclusion Criteria

• Pre-stroke mRS of 3, 4 or 5 (indicating moderate to severe pre-morbid disability)

• Haemorrhagic stroke or transient ischaemic attack

• Severe stroke (NIHSS > 16)

• Comorbid progressing neurological conditions

• Severe heart failure or unstable coronary conditions

• Other drug or intervention trial

Data Collection

REDCap will be the data management system used. It is a web-based electronic data entry and management system. The electronic Case Report Form (eCRF) will be completed for each study participant summarising all clinical screening and study data.

In addition to the main data set, a number of sub-studies will concurrently run and will include genetic, motor evoked potential and imaging analyses in selected regions.

Intervention

The intervention will be provided in both mild and moderate patients (Baseline randomisation NIHSS score). In each group, there will be 4 pre-specified therapy protocols that will be implemented by physiotherapists and nurses. Patients will be randomised to receive one of the 4 treatment protocols for the duration of their acute hospital stay. Time in therapy and frequency of sessions will vary across groups and may require a reorganisation or physiotherapy and nursing care, however, will not require the employment of additional staff to implement. No specialised equipment is required to implement the protocol by the staff.

Follow up assessments

Patients will be followed up at 3 and 6 months by an assessor who has been blinded to treatment arm and may occur in the clinic and the community.