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Trial registered on ANZCTR


Registration number
ACTRN12619000557134
Ethics application status
Approved
Date submitted
22/03/2019
Date registered
10/04/2019
Date last updated
7/10/2021
Date data sharing statement initially provided
10/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to Determine the Optimal early mobility Training after StrokE (AVERT DOSE)
Scientific title
A Phase 3, Multi Arm, Multi Stage, Covariate Adjusted, Response Adaptive, Randomised Trial to Determine Optimal Early Mobility Training after Stroke.
Secondary ID [1] 296961 0
Nil known
Universal Trial Number (UTN)
U1111-1221-2442
Trial acronym
AVERT DOSE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Stroke 310925 0
Condition category
Condition code
Stroke 309587 309587 0 0
Ischaemic
Physical Medicine / Rehabilitation 310717 310717 0 0
Physiotherapy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
4 groups of differing doses of mobility training provided by physiotherapists and nurses directly in the acute phase of stroke recovery (until discharge or until 14 days post stroke (whichever occurs first.)

Participants are randomised to receive between 1 and 4 sessions of mobility training per day, at an intensity that is tolerable to the participant. Session times are short, no longer than 20 minutes. Intervention is provided by the Physiotherapists at tolerable dose, noted as mild moderate and vigorous intensity as determined by the BORG and physiological measures including heart and respiratory rates, O2 saturation and Blood pressure. Frequency of sessions are fixed depending on randomisation group. The details of the therapy groups, timing and intensity is outlined in an intervention protocol that is provided to staff providing the therapy. To avoid unblinding or further treatment bias, this protocol will remain inhouse to avoid contamination, until trial end at which time the details will be published.
All aspects of all sessions will be recorded on a therapy recording form and entered into online data base. Sessions will be monitored for adherence to protocol by the research team.
Intervention code [1] 313232 0
Rehabilitation
Comparator / control treatment
A Pre specified dose of mobility training has been determined as the control group. This dose has been informed by the results of the AVERT trial and selected by the trial statistician. All researchers, trial staff and participants are blinded to which group has been chosen as the control group to further avoid bias.
Control group
Dose comparison

Outcomes
Primary outcome [1] 318546 0
The proportion of participant achieving a favourable outcome of no or little disability assessed using modified Rankin Score (mRS) of 0-2 at 3 months post stroke
Timepoint [1] 318546 0
3 months post stroke
Secondary outcome [1] 365336 0

Safety - All complications during the 14 day intervention period. Patient reported and medical record review of all adverse events and serious adverse events, for example, falls, stroke progression, pneumonia.
Timepoint [1] 365336 0
14 days post stroke
Secondary outcome [2] 365337 0
Safety - All immobility and stroke related complications up to 3 months. Patient reported and medical record review of all adverse events and serious adverse events, for example, falls, stroke progression, pneumonia.
Timepoint [2] 365337 0
3 months post stroke
Secondary outcome [3] 365338 0
Safety - All Serious Adverse Events up to 6 months Patient reported and medical record review of all adverse events and serious adverse events, for example, falls, stroke progression, pneumonia.
Timepoint [3] 365338 0
6 Months post stroke
Secondary outcome [4] 365339 0
Degree of disability assessed using the modified Rankin Scale (mRS) across the full ordinal scale.
Timepoint [4] 365339 0
3 months post stroke
Secondary outcome [5] 365340 0
Time until participant is able to walk 50 metres independently. (with or without gait aid)
Timepoint [5] 365340 0
50m walk achieved assessed at time of discharge, 3 and 6 months post stroke.
Secondary outcome [6] 365341 0
Walking speed post stroke assessed using the 6 Metre Walk Test (6MWT)
Timepoint [6] 365341 0
Assessed at discharge, 3 and 6 months post stroke
Secondary outcome [7] 365342 0
Quality of life post stroke assessed using EQ-5D-5L. Additionally, the HADS or SADsH10 (for aphasic participants) will be collected.
Timepoint [7] 365342 0
3 and 6 months post stroke
Secondary outcome [8] 365343 0
Cost effectiveness analysis using the favourable outcome (mRS 0-2) combined with resource utilisation data collected throughout the trial. Cost effectiveness ratios will be reported as cost per favuourable mRS outcome and cost per Quality Adjested Life Years (QALYs) gained based on EQ-5D-5L. Differences between resource use and patient out of pocket costs will be collected via a detailed cost questionnaire administered by the blinded assessor at the follow up visits.
Timepoint [8] 365343 0
6 months post stroke
Secondary outcome [9] 368687 0
Cost Utility analysis based on QOL measured at QALY gains at 6 months. Measured using the 1) mapped utility from baseline mRS (for primary analysis); and 2) score using the baseline EQ-5D-5L (for sensitivity analysis).
Timepoint [9] 368687 0
6 months post stroke

Eligibility
Key inclusion criteria
Ischaemic stroke (first or recurrent)
Aged 18 years or over
Ability to be enrolled within 48 hrs of onset of stroke symptoms.
Mild (NIHSS 0-7) or moderate stroke severity (NIHSS 8 - 16)
Pre stroke mRS of 0-2
Participants are medically stable at the time of enrollment (physiological criteria = Patient rousable, SBP>120mmHg and <180MmmHg, 02 saturation >92%, HR >40 and <100, Temperature <38.5 degrees
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with pre stroke mRS of 3,4, or 5
Diagnosis of haemorrhagic stroke or transient ischaemic attack
Severe stroke (NIHSS >16)
Co morbid progressive neurological conditions
Severe heart failure or unstable coronary conditions tat are judged by the investigator to impose a hazard to the participant is involved in the trial
Concurrent diagnosis of rapidly deteriorating disease (eg terminal cancer)
Deterioration following admission resulting in a documented clinical decision for palliative treatment or immediate surgery
A lower limb fracture or other disability which deems the participant unable to participate in mobility training
Patients with no evident mobility problems
Patients expected to be discharged within 3 days of trial enrollment
Current participation in a drug or other intervention trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A separate adaptive randomisation module algorithmically combining covariate adjustment with response adaptation in intervention arms is implemented within REDCap application programming interface.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Covariate adjusted, response adaptive multi arm, multi stage, randomisation design.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Primary The mRS scores at 3 months will be dichotomised, with scores of 0-2 reflecting ‘favourable outcome’ and scores of 3-6 reflecting ‘poor outcome’. In our primary analysis we will use the randomisation-based analysis with permutation test of the difference between the single intervention arm selected to proceed to Stage 2 and the pre-specified reference arm individually for each stratum (stratum-specific one-sided family-wise p=0.025). The non-parametric permutation or randomisation tests used for analysis in proposed adaptive design, test the null hypothesis that the assignment of treatments has no effect on the responses (outcome) of the participants in the study. The effect sizes will be reported as risk differences between the probabilities of a favourable outcome. In case the same treatment regimen appears optimal in both strata, a pooled risk difference measure will be derived using Mantel-Haenszel method.
Secondary analyses will be conducted using regression modelling. Despite the adaptive nature of the randomisation used in AVERT DOSE, maximum likelihood estimations using, e.g.Wald test, can be applied if the appropriate correction for potential estimation bias is undertaken. Full dose-response exploratory analyses will be conducted across all dose regimens.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2019
Actual
22/09/2019
Date of last participant enrolment
Anticipated
1/07/2022
Actual
Date of last data collection
Anticipated
1/01/2023
Actual
Sample size
Target
2700
Accrual to date
72
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 12810 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 12811 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 12812 0
The Alfred - Prahran
Recruitment hospital [4] 13467 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [5] 13468 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [6] 13469 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [7] 20674 0
Joondalup Health Campus - Joondalup
Recruitment hospital [8] 20675 0
Albury Wodonga Health - Albury campus - Albury
Recruitment hospital [9] 20676 0
John Hunter Hospital - New Lambton
Recruitment hospital [10] 20677 0
Box Hill Hospital - Box Hill
Recruitment hospital [11] 20678 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [12] 20679 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [13] 20680 0
Royal Perth Hospital - Perth
Recruitment hospital [14] 20681 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 25280 0
3084 - Heidelberg
Recruitment postcode(s) [2] 25281 0
3050 - Parkville
Recruitment postcode(s) [3] 25282 0
3004 - Prahran
Recruitment postcode(s) [4] 26080 0
6150 - Murdoch
Recruitment postcode(s) [5] 26081 0
4575 - Birtinya
Recruitment postcode(s) [6] 26082 0
3220 - Geelong
Recruitment postcode(s) [7] 35473 0
6027 - Joondalup
Recruitment postcode(s) [8] 35474 0
2640 - Albury
Recruitment postcode(s) [9] 35475 0
2305 - New Lambton
Recruitment postcode(s) [10] 35476 0
3128 - Box Hill
Recruitment postcode(s) [11] 35477 0
4102 - Woolloongabba
Recruitment postcode(s) [12] 35478 0
3065 - Fitzroy
Recruitment postcode(s) [13] 35479 0
6000 - Perth
Recruitment postcode(s) [14] 35480 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 21156 0
United Kingdom
State/province [1] 21156 0
NA
Country [2] 21157 0
India
State/province [2] 21157 0
NA
Country [3] 21158 0
New Zealand
State/province [3] 21158 0
NA
Country [4] 21364 0
Ireland
State/province [4] 21364 0
NA
Country [5] 24177 0
Brazil
State/province [5] 24177 0
NA
Country [6] 24178 0
Malaysia
State/province [6] 24178 0
NA
Country [7] 24179 0
Singapore
State/province [7] 24179 0
NA

Funding & Sponsors
Funding source category [1] 301531 0
Government body
Name [1] 301531 0
National Health and Medical Research Council (NHMRC)
Country [1] 301531 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
The Florey Institute of Neuroscience and Mental Health
Address
245 Burgundy Street, Heidelberg, Victoria 3084, Australia.
Country
Australia
Secondary sponsor category [1] 301233 0
None
Name [1] 301233 0
Address [1] 301233 0
Country [1] 301233 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302270 0
Austin Health
Ethics committee address [1] 302270 0
Studley road, Heidelberg, Victoria 3084
Ethics committee country [1] 302270 0
Australia
Date submitted for ethics approval [1] 302270 0
31/10/2018
Approval date [1] 302270 0
07/03/2019
Ethics approval number [1] 302270 0
HREC/43406/Austin-2018

Summary
Brief summary
The aim of this study is to define the dose of early rehabilitation intervention that provides the most benefit for people with ischaemic stroke of mild and moderate severity.
4 separate rehabilitation intervention regimens (different number, length and intensity of training sessions) will be implemented by physiotherapists and nurses in stroke units immediately post stroke. Participants will be followed up at 3 and 6 months post stroke. 2,700 patients with mild to moderate stroke will be recruited in Australia, New Zealand, Singapore, Malaysia, India and the UK.
We hypothesise that the optimal dose intervention regimen will result in an improved outcome at 3 months post stroke, with less complications at 14 days and better quality of life at 6 months post stroke.


Trial website
Not applicable
Trial related presentations / publications
Not applicable
Public notes

Contacts
Principal investigator
Name 89642 0
Prof Julie Bernhardt
Address 89642 0
The Florey Institute of Neuroscience and Mental Health
245 Burgundy Street Heidelberg VIC 3084
Country 89642 0
Australia
Phone 89642 0
+61 3 9035 7072
Fax 89642 0
NA
Email 89642 0
[email protected]
Contact person for public queries
Name 89643 0
Ms Fiona Ellery
Address 89643 0
The Florey Institute of Neuroscience and Mental Health
245 Burgundy Street Heidelberg VIC 3084
Country 89643 0
Australia
Phone 89643 0
+61 3 9035 7042
Fax 89643 0
NA
Email 89643 0
[email protected]
Contact person for scientific queries
Name 89644 0
Prof Julie Bernhardt
Address 89644 0
The Florey Institute of Neuroscience and Mental Health
245 Burgundy Street Heidelberg VIC 3084
Country 89644 0
Australia
Phone 89644 0
+61 3 9035 7072
Fax 89644 0
NA
Email 89644 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All de identified IPD
When will data be available (start and end dates)?
Following publication, no end date
Available to whom?
Researchers who provide a methodologically sound proposal at the discretion of the trial management committee
Available for what types of analyses?
To achieve aims of approved proposals and IPD meta- analyses.
How or where can data be obtained?
Access via principal investigator following signature of data access agreement.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA phase III, multi-arm multi-stage covariate-adjusted response-adaptive randomized trial to determine optimal early mobility training after stroke (AVERT DOSE).2023https://dx.doi.org/10.1177/17474930221142207
N.B. These documents automatically identified may not have been verified by the study sponsor.