Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000374662
Ethics application status
Approved
Date submitted
26/03/2023
Date registered
13/04/2023
Date last updated
7/04/2024
Date data sharing statement initially provided
13/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
ORCAS: Observing Recovery After Stroke
Scientific title
ORCAS: A prospective, single-site, longitudinal, mixed methods, observational study of motor recovery after stroke
Secondary ID [1] 309287 0
None
Universal Trial Number (UTN)
Trial acronym
ORCAS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 329450 0
Condition category
Condition code
Stroke 326386 326386 0 0
Ischaemic
Stroke 326387 326387 0 0
Haemorrhagic
Physical Medicine / Rehabilitation 326388 326388 0 0
Physiotherapy
Physical Medicine / Rehabilitation 326389 326389 0 0
Occupational therapy

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is a prospective, single-site, longitudinal, mixed methods study observing motor recovery after stroke. The purpose of the study is to progress three prediction tools designed by our team along the development, validation, and implementation pipeline. It will use a combination of clinical and imaging features to develop IMPRESS (Intelligent Multimodal imaging platform to PREdict Stroke motor outcomeS), a prediction tool for upper and lower limb motor outcomes after stroke. The study will also externally validate TWIST (Time to Walking Independently after STroke), a previously developed and internally validated prediction tool for walking recovery after stroke. The IMPRESS and TWIST tools are not being used in clinical practice, and the prediction information that they generate will not be shared with participants. The study will also further develop and improve the neurophysiology component of the PREP2 (Predict REcovery Potential) upper limb prediction tool, which has already been externally validated and implemented in clinical practice. Participants in this study will receive a PREP2 prediction for their upper limb motor outcome as part of their routine clinical care.

Participants in the ORCAS study will be asked to complete the following assessments in addition to usual clinical care. The combination of assessments they are asked to complete will depend on which prediction tools are suitable for them, and which prediction tools they have consented to participating in. Potential participants will be told which prediction tools are suitable for them, and they can choose which suitable tools they want to participate in at the time of consent.

Baseline upper limb clinical assessments will be made within the first week post-stroke for the IMPRESS and PREP2 tools. These are listed below and will be carried out by a trained researcher at Auckland City Hospital. The upper limb assessment is expected to take up to 1 hour.
Fugl-Meyer Upper Extremity scale
Action Research Arm Test
Bimanual Coordination After Stroke Scale
Grooved Pegboard Test
Grip and pinch force
Cutaneous sensation at the base of the thumb using monofilaments

Baseline lower limb clinical assessments will be made within the first week post-stroke for the IMPRESS and TWIST tools. These are listed below and will be carried out by a trained researcher at Auckland City Hospital. The lower limb assessment is expected to take up to 30 minutes.
Functional Ambulation Category Score
Lower limb muscle strength with Medical Research Council grading
Berg Balance Scale

Baseline cognitive clinical assessments will be made within the first week post-stroke for the IMPRESS and TWIST tools. These are listed below and will be carried out by a trained researcher at Auckland City Hospital. The cognitive assessment is expected to take up to 45 minutes.
Star Cancellation Test
Broken Hearts Test
Montreal Cognitive Assessment

Baseline neurophysiology assessment will be carried within the first week post-stroke for the PREP2 tool. This involves recording surface electromyography from the extensor carpi radialis, flexor carpi radialis, first dorsal interosseous, and abductor digiti minimi muscles of the paretic forearm and hand. This assessment will be carried out by a trained researcher using Transcranial Magnetic Stimulation at Auckland City Hospital. The researcher will use single-pulse TMS to record motor evoked potentials in the four muscles listed above. This single session is expected to take up to 1 hour and will be carried out within the first week post-stroke.

Follow-up assessments at 4, 6, 9 and 16 weeks post-stroke will be carried out for the IMPRESS and TWIST tools. A trained assessor will complete this assessment either in person at Auckland City Hospital or by telephone if they have left hospital. The assessments are listed below, and each follow-up session is expected to last up to 15 minutes.
Functional Ambulation Category score
Any falls since last assessment
Use of walking aids such as stick or low walking frame
Place of residence

Follow-up assessments at 12 and 26 weeks post stroke will be carried out for the IMPRESS, TWIST and PREP2 tools, as noted for each measure below. A trained assessor will complete these assessments in person either at Auckland City Hospital or at the University of Auckland. The assessments are listed below, and each follow-up session is expected to last between 30 and 90 minutes, depending on the combination of assessments completed.
Action Research Arm Test – IMPRESS and PREP2
Fugl-Meyer Upper Extremity score – IMPRESS and PREP2
Modified Rankin Scale – IMPRESS, TWIST, and PREP2
Functional Ambulation Category score – IMPRESS and TWIST
6 minute walk test and 10 metre walk test – TWIST
Spatiotemporal gait characteristics measured with a GaitRite gait mat – TWIST
Additionally, participants in the TWIST prediction tool will also be asked to wear an activity monitor on their wrist for 72 hours to measure the number of steps they take during this time period.

Related ACTRN registrations for the tools are:
TWIST ACTRN12620001366943
PREP ACTRN12619000225112
Intervention code [1] 325722 0
Diagnosis / Prognosis
Comparator / control treatment
No control group as this is an observational study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334245 0
Primary upper limb outcome. Upper limb activity capacity assessed with the Action Research Arm Test (ARAT). A trained assessor will complete this assessments in person either at Auckland City Hospital or at the University of Auckland.
Timepoint [1] 334245 0
12 weeks post-stroke
Primary outcome [2] 334246 0
Primary lower limb outcome. Week post-stroke at which independent walking is achieved, defined as a Functional Ambulation Category (FAC) score of 4 or 5 (out of a maximum score of 5). A trained assessor will complete this assessment either in person at Auckland City Hospital or by telephone if they have left hospital.
Timepoint [2] 334246 0
The FAC score will be evaluated at 4, 6, 9, 12, 16 and 26 weeks post-stroke, and will be considered to have been achieved at the earliest time point when the participant is able to walk independently, as defined above.
Secondary outcome [1] 420300 0
Upper limb activity capacity assessed with the Action Research Arm Test (ARAT). A trained assessor will complete this assessments in person either at Auckland City Hospital or at the University of Auckland.
Timepoint [1] 420300 0
26 weeks post-stroke
Secondary outcome [2] 420301 0
Upper limb impairment assessed with the Fugl-Meyer Upper Extremity Scale (FM-UE). A trained assessor will complete this assessments in person either at Auckland City Hospital or at the University of Auckland.
Timepoint [2] 420301 0
12 and 26 weeks post-stroke
Secondary outcome [3] 420303 0
Functional Ambulation Category (FAC) score. A trained assessor will complete this assessment either in person at Auckland City Hospital or by telephone if they have left hospital.
Timepoint [3] 420303 0
4, 6, 9, 12, 16, and 26 weeks post-stroke
Secondary outcome [4] 420304 0
Any falls since last assessment. A trained assessor will complete this assessment either in person at Auckland City Hospital or by telephone if they have left hospital.
Timepoint [4] 420304 0
4, 6, 9, 12, 16, and 26 weeks post-stroke
Secondary outcome [5] 420305 0
Use of walking aid (e.g., walking stick, low walking frame). A trained assessor will complete this assessment either in person at Auckland City Hospital or by telephone if they have left hospital.
Timepoint [5] 420305 0
4, 6, 9, 12, 16, and 26 weeks post-stroke
Secondary outcome [6] 420306 0
Place of residence, categorised as home alone, home not alone, rehabilitation facility or residential care. A trained assessor will complete this assessment either in person at Auckland City Hospital or by telephone if they have left hospital.
Timepoint [6] 420306 0
4, 6, 9, 12, 16, and 26 weeks post-stroke
Secondary outcome [7] 420319 0
Walking endurance assessed with the 6 Minute Walk Test (6MWT). A trained assessor will complete this assessment either in person at Auckland City Hospital or at the University of Auckland.
Timepoint [7] 420319 0
12 and 26 weeks post-stroke.
Secondary outcome [8] 420320 0
Walking speed assessed with the 10 Metre Walk Test (10MWT). A trained assessor will complete this assessment in person at Auckland City Hospital or at the University of Auckland
Timepoint [8] 420320 0
12 and 26 weeks post-stroke.
Secondary outcome [9] 420321 0
Spatiotemporal gait characteristics measured with a GaitRite gait mat. A trained assessor will complete this assessment either in person at Auckland City Hospital or at the University of Auckland.
Timepoint [9] 420321 0
12 and 26 weeks post-stroke.
Secondary outcome [10] 420322 0
The number of steps taken in a 72 hour period, measured with an activity monitor worn on the wrist. A trained assessor will set the participant up with the activity monitor at the completion of the walking assessments occurring in person at Auckland City Hospital or the University of Auckland. The trained assessor will then receive the activity monitor from the participant after the 72 hour period.
Timepoint [10] 420322 0
12 and 26 weeks post-stroke.
Secondary outcome [11] 420327 0
Disability measured with the modified Rankin Scale (mRS). A trained assessor will complete this assessment either in person at Auckland City Hospital or the University of Auckland.
Timepoint [11] 420327 0
12 and 26 weeks post-stroke.
Secondary outcome [12] 420335 0
Semi-structured interviews identifying perceived risks and benefits of having walking prediction information available and to identify potential barriers and facilitators to implementing TWIST in routine clinical care. A trained assessor will conduct the interviews either in hospital, at the patient's home, via telephone or via zoom videoconference as decided by the patient.
Timepoint [12] 420335 0
2 weeks post-stroke.

Eligibility
Key inclusion criteria
1. At least 18 years old
2. Ischaemic stroke or intracerebral haemorrhage within the previous 7 days
3. New upper and/or lower limb motor symptoms:
3a. Participants with a shoulder abduction and finger extension score (SAFE) less than or equal to 8 at 3 days are eligible for upper limb assessments
3b. Participants with a FAC score < 4 and lower limb weakness assessed with the Medical Research Council (MRC) strength grade < 5 at 1 week post-stroke are eligible for lower limb assessments
4. Previous stroke is allowed provided the patient had no residual upper or lower limb weakness and was walking independently prior to the new stroke
5. Treatment with thrombolysis or endovascular thrombectomy is allowed
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria for the whole study
i. Subarachnoid haemorrhage or cerebellar stroke
ii. Severe cognitive or communication impairment precluding informed consent, based on clinical team expertise
iii. Expected life span less than 6 months based on the assessment of the patient’s clinical team
iv. Residing out of region precluding in-person assessment

Exclusion criteria for specific parts of the study
i. Participants who have had an intracerebral haemorrhage will be excluded from the IMPRESS prediction tool dataset
ii. Participants with pre-existing upper limb motor impairment determined by a SAFE score less than or equal to 8 will be excluded from upper limb assessments
iii. Participants who were unable to walk independently determined by FAC score < 4, or required the use of a walking frame prior to stroke will be excluded from lower limb assessments
iv. Participants who are unable to receive TMS will be excluded from the TMS assessment. These participants will be identified with a safety screening checklist checked by a neurologist.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
IMPRESS prediction tool
A sample size of 180 participants with stroke will be combined with retrospective data from previous studies by the group
Most participants will have received routine CT imaging from Auckland City Hospital
Routine CT imaging will be used to generate pseudo-MRI using convolutional neural networks
Pseudo-MRI will undergo further preprocessing, lesion segmentation, registration, and biomarker extraction
Machine learning techniques will be used to classify the following 3 month outcomes:
i. PREP2 predicted upper limb motor outcome
ii. FAC score
iii. mRS score
The input measures to the machine learning algorithms will be:
i. Imaging biomarkers
ii. Baseline clinical scores (NIHSS, FM-UE, SAFE score, FAC, Berg Balance Scale, MRC strength for knee extension)
iii. Baseline stroke information and demographics (stroke classification, age, comorbidities)
The validation method will be as follows:
i. 70% training : 30% testing
ii. Nested 10-fold cross-validation will be performed within the 70% training subset
iii. Synthetic data oversampling techniques may be used to correct for unbalanced outcome groups

TWIST prediction tool
The primary lower limb outcome is the time at which independent walking, defined as FAC score of at least 4, is achieved, measured as weeks post-stroke
A sample size of up to 125 participants with stroke will be used for this analysis
With 100 participants, and no fewer than 27/100 participants recovered or not recovered at any time point we will be able to estimate a C statistic of 0.7 or greater, with 95% confidence limits as small as 0.15
Binary logistic regression modelling will be used to evaluate how accurately the TWIST score predicts independent walking at 4, 6, 9, 12 and 26 weeks post-stroke
Calibration plots will be used to visually inspect model performance, and the Hosmer-Lemeshow test will be used with p < 0.05 considered evidence of miscalibration of the model.
The TWIST prediction tool as a whole will be considered externally validated if it makes accurate predictions for at least 85% of participants at a minimum of 3 time points post-stroke
A subset of participants will be invited to complete interviews to understand their perceptions of walking prediction information
Interviews will be audio recorded and transcribed
NVivo will be used to carry out a thematic analysis for the perceived benefits or risks of walking recovery predictions being available
This will allow identification of potential facilitators and barriers in implementing TWIST in routine clinical care, which can be evaluated in a subsequent study

PREP2 prediction tool
A sample size of up to 180 participants with stroke will be used for a classification and regression tree (CART) analysis
A CART analysis produces a decision tree without any a priori information about which of the variables to include or their order
The following PREP2 predictor variables will be included for analysis:
i. SAFE score, binarized as greater than and equal to 5 and <5
ii. Age, binarized as greater than and equal to 80 and <80
iii. MEP status, binarized as MEP+ and MEP-
iiii. NIHSS
A novel compositional neurophysiological variable will be derived from MEP persistence calculated for each muscle at each stimulation intensity
The novel compositional neurophysiological variable will be added to the CART analysis with the existing PREP2 variables
The positive and negative predictive value for upper limb outcome predictions using the additional compositional neurophysiological information will be compared with the positive and negative predictive value of the PREP2 predicted outcomes

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
24/04/2023
Actual
4/05/2023
Date of last participant enrolment
Anticipated
15/12/2025
Actual
Date of last data collection
Anticipated
15/06/2026
Actual
Sample size
Target
180
Accrual to date
52
Final
Recruitment outside Australia
Country [1] 25344 0
New Zealand
State/province [1] 25344 0

Funding & Sponsors
Funding source category [1] 313482 0
Government body
Name [1] 313482 0
Health Research Council of New Zealand
Country [1] 313482 0
New Zealand
Funding source category [2] 313484 0
Charities/Societies/Foundations
Name [2] 313484 0
Neurological Foundation of New Zealand
Country [2] 313484 0
New Zealand
Funding source category [3] 313485 0
Charities/Societies/Foundations
Name [3] 313485 0
Auckland Medical Research Foundation
Country [3] 313485 0
New Zealand
Funding source category [4] 313486 0
Charities/Societies/Foundations
Name [4] 313486 0
Kelliher Charitable Trust
Country [4] 313486 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
Private Bag 92019
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 315255 0
None
Name [1] 315255 0
Address [1] 315255 0
Country [1] 315255 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312673 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 312673 0
Ethics committee country [1] 312673 0
New Zealand
Date submitted for ethics approval [1] 312673 0
23/02/2023
Approval date [1] 312673 0
17/03/2023
Ethics approval number [1] 312673 0
2023 EXP 13889

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125514 0
Prof Cathy Stinear
Address 125514 0
Department of Medicine
University of Auckland
Private Bag 92019
Auckland 1142
Country 125514 0
New Zealand
Phone 125514 0
+64 99233779
Fax 125514 0
Email 125514 0
[email protected]
Contact person for public queries
Name 125515 0
Cathy Stinear
Address 125515 0
Department of Medicine
University of Auckland
Private Bag 92019
Auckland 1142
Country 125515 0
New Zealand
Phone 125515 0
+64 99233779
Fax 125515 0
Email 125515 0
[email protected]
Contact person for scientific queries
Name 125516 0
Cathy Stinear
Address 125516 0
Department of Medicine
University of Auckland
Private Bag 92019
Auckland 1142
Country 125516 0
New Zealand
Phone 125516 0
+64 99233779
Fax 125516 0
Email 125516 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?
Anonymised individual participant data underlying published results.
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years after publication of the main study results.
Available to whom?
Case by case basis at the discretion of the principal investigator.
Available for what types of analyses?
IPD meta-analyses.
How or where can data be obtained?
Data can be requested by contacting the principal investigator by email: [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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