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Trial registered on ANZCTR


Registration number
ACTRN12619001059156p
Ethics application status
Submitted, not yet approved
Date submitted
13/06/2019
Date registered
30/07/2019
Date last updated
30/07/2019
Date data sharing statement initially provided
30/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
RETHINK: a Cohort study to REconsider the Factors that INfluence StroKe Recovery.
Scientific title
RETHINK: a cohort study to measure biomarker and psycho-social determinants that influence upper limb motor recovery in ischaemic stroke patients.
Secondary ID [1] 298295 0
APP1182075
Universal Trial Number (UTN)
NIL
Trial acronym
RETHINK
Linked study record
NIL

Health condition
Health condition(s) or problem(s) studied:
Ischaemic stroke 312923 0
Condition category
Condition code
Stroke 311416 311416 0 0
Ischaemic

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This observational study will observe psychological determinants and blood/microbiome biomarkers that influence ischaemic stroke neurological domain specific outcomes, (for Motor Function Upper /Lower limb; Cognitive- Aphasia; Cognitive- Neglect; Cognitive-any deficit; Sensory;Depression ). Patients will be asked to provide a blood sample and faecal sample on enrolment. Depending on their domain of deficit, they will be asked to provide additional blood and faecal samples at 3, 6 ,12 and 24 months follow up time-points. All participants will be asked for permission for study nurses to access their clinical in hospital data, and all will be asked to complete an online survey about quality of life at 12 and 24 months. Follow up clinical assessments will be conducted int he participants homes or a community clinic setting.

For the qualitative arm of the study- All participants from each domain group will be invited on enrolment to take part in 2 face to face or audio recorded telephone interviews, at 12 and 24 months post enrolment. Recruitment will continue until 10 stroke survivors from each domain have been recruited with the aim to recruit 70 stroke cases (10 from each domain). Duration of each interview will be approximately 30 minutes.
Intervention code [1] 314736 0
Not applicable
Comparator / control treatment
There is no control group in this observational study. Comparisons will be made between those stroke survivors who have better outcomes versus those who have worse outcomes.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320398 0
Upper limb Motor recovery outcomes as assessed by Fugl-Meyer (FM) Assessment (FM-UL) upper limb motor score
Timepoint [1] 320398 0
Primary time point is 3 months post stroke enrolment
Primary end-points is 3,6,12 and 24 months post enrolment
Primary outcome [2] 320400 0
Lower limb Motor recovery outcomes as assessed by Fugul-Meyer (FM) Assessment lower limb (FM-LL) motor score
Timepoint [2] 320400 0
Primary time point is 3 months post stroke enrolment
Primary end-points is 3,6,12 and 24 months post enrolment
Secondary outcome [1] 371472 0
Cognitive-aphasia outcomes assessed by Bedside Western Aphasia Battery-Revised (WAB-R)
Timepoint [1] 371472 0
Enrolment 5-7 days post stroke event
Secondary end-points 6 months post enrolment
Secondary outcome [2] 371476 0
Cognitive-neglect recovery outcomes assessed by Star Cancellation Test (SCT)
Timepoint [2] 371476 0
Enrolment 5-7 days post stroke event
Secondary end-points 6 months post enrolment
Secondary outcome [3] 371479 0
Cognitive-any deficit recovery outcomes measured by MoCa
Timepoint [3] 371479 0
Enrolment 5-7 days post stroke event
Secondary end-points 12, and 24 months post enrolment
Secondary outcome [4] 371482 0
Depression as assessed by Patient Health Questionnaire 9 (PHQ9) score < 9 mild or no depression
Timepoint [4] 371482 0
Enrolment 5-7 days post stroke event
Secondary end-points 3 and 2 months post enrolment
Secondary outcome [5] 371489 0
Gut microbiota DNA as assessed by faecal samples.
Timepoint [5] 371489 0
Enrolment Collected within 24 hours of event (but up to 48 hours)
Secondary end-points 3 months post enrolment
Secondary outcome [6] 371490 0
Fatigue measured by Daily Fatigue Impact Scale (DFI-S),
Timepoint [6] 371490 0
Enrolment 5-7 days post stroke event
Secondary end points 12, and 24 months post enrolment
Secondary outcome [7] 371491 0
Frailty post stroke assessed by Fried Frailty Index (FFI)
Timepoint [7] 371491 0
Enrolment 5-7 days post stroke event
Secondary end-points 12, and 24 months post enrolment
Secondary outcome [8] 371932 0
Blood biomarkers as assessed by Angiopt-1 blood concentrations via serum assay
Timepoint [8] 371932 0
Enrolment 5-7 days post stroke event
Secondary end-points 3, 6, 12, and 24 months post enrolment
Secondary outcome [9] 372934 0
Cognitive-any deficit recovery outcomes measured by Cogstate Brief Battery Test
Timepoint [9] 372934 0
Enrolment 5-7 days post stroke event
Secondary end-points 12, and 24 months post enrolment
Secondary outcome [10] 373143 0
Blood biomarkers as assessed by Brain derived neurotrophic factor blood concentrations via serum assay
Timepoint [10] 373143 0
Enrolment 5-7 days post stroke event
Secondary end-points 3, 6, 12, and 24 months post enrolment

Eligibility
Key inclusion criteria
Ischaemic stroke cases defined in consultation with specialist neurologist and based on routine care imaging (CT and/or MRI); greater than 18 years old and have persistent symptoms of any deficit for greater than 5-7 days. Stroke is defined by standard definitions and then stratified into groups according to domains of deficit. Each recovery domain will be defined by clinical symptom items as per National Institute of Health Stroke Scale (NIHSS). Parameters include deficit symptoms persisting for greater than 5-7 days.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Severe illnesses i.e. palliative medical management in place, another neurological condition, seizure activity that prevent NIHSS assessment, patients unable to provide consent due to communication deficits or have no access to appropriate substitute decision maker, carer or in the case of non-English speaking case, a translator. For study subjects who agree to participate in the faecal microbiome arm, exclusion will include a history of inflammatory bowel disease or antibiotic use within 30 days of admission.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample size: Assuming a conservative 50% of the cohort will have an excellent outcome (determined by the NIHSS), and using alpha=0.05, a power of 80% to detect a clinically relevant risk ratio of 0.8, we will require a sample size of 774. However, as we expect that approximately 20% drop-out prior to completion, we need to recruit a total of 970 participants. Significance will be set at p<0.05. All analyses will be undertaken with STATA (version 15). Regarding the primary aim, to characterise biomarkers and psychosocial determinants that associate with motor recovery at 4 time points and test for association with motor recovery and favourable/unfavourable outcome. The total Fugl-Meyer (FM) Assessment, upper limb (FM-UL) and lower limb (FM-LL) motor scores at different time point will be calculated. Continuous variables are presented as mean ± SD for normally distributed data and as median with interquartile range for skewed data. Repeated measures analysis of variance or a liner mixed model will be applied to analyse the changes of FM over time. Furthermore, measures for the motor recovery domain group will be compared between patients with severe deficit (according to the FM score) and those with minor or no deficit using CHI 2 and Mann-Whitney U tests. To assess the association of psychosocial determinants with stroke motor recovery over time, generalized estimating equations (GEE) analysis will be performed adjusting for baseline characteristics. Any cut-offs for secondary analysis (Favourable and Unfavourable outcome) will be determined after consideration of sample size and distribution of the data. Plasma Angiopt-1 concentration levels will be measured and analysed for association with unfavourable outcome at 3 months, 1 and 2 years between stroke survivors with favourable to unfavourable FM-UL outcomes using general linear models. A mixed effects linear regression model will be used to determine the probability of attaining a clinically meaningful change as a function of follow up time-points and a combination of sets of biomarkers and/or psychosocial determinants of a favourable or meaningful outcome, adjusted for severity, age, gender and premorbid ranking. In addition, we will assess community-wide differences in microbiome composition (ß diversity118) between groups defined by these outcomes using a permutation-based multiple analysis of variance test (PERMANOVA) of Bray-Curtis dissimilarities. Between group differences in faecal OTU abundance will be identified using negative binomial regression. We will also evaluate a multivariable model including important outcome predictors including age, gender, baseline NIHSS, history of stroke, pre-stroke disability, infarct size from CT, and thrombolysis treatment.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/10/2020
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
970
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA
Recruitment hospital [1] 13993 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 13994 0
The Townsville Hospital - Douglas
Recruitment hospital [3] 13995 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 26772 0
6009 - Nedlands
Recruitment postcode(s) [2] 26773 0
4814 - Douglas
Recruitment postcode(s) [3] 26774 0
5000 - Adelaide
Recruitment outside Australia
Country [1] 21602 0
Sweden
State/province [1] 21602 0
Gothenburg
Country [2] 21603 0
United States of America
State/province [2] 21603 0
Virginia

Funding & Sponsors
Funding source category [1] 302838 0
Government body
Name [1] 302838 0
National Health Medical Research Council
Country [1] 302838 0
Australia
Primary sponsor type
University
Name
University of Technology Sydney
Address
Research & Innovation Office
University of Technology, Sydney
E: Research.Ethics@uts.edu.au
PO Box 123, BROADWAY NSW 2007
[Level 14, Building 1, Broadway Campus]
Country
Australia
Secondary sponsor category [1] 302784 0
None
Name [1] 302784 0
Address [1] 302784 0
Country [1] 302784 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303416 0
University of Technology Sydney, Human Ethics Committee
Ethics committee address [1] 303416 0
Ethics committee country [1] 303416 0
Australia
Date submitted for ethics approval [1] 303416 0
05/04/2019
Approval date [1] 303416 0
Ethics approval number [1] 303416 0

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

Contacts
Principal investigator
Name 93602 0
Prof Jane Margaret Maguire
Address 93602 0
235 Jones street
Building 10
Faculty of Health
University of Technology Sydney
Sydney NSW 2007
Country 93602 0
Australia
Phone 93602 0
+61295145971
Fax 93602 0
Email 93602 0
jane.maguire@uts.edu.au
Contact person for public queries
Name 93603 0
Jane Margaret Maguire
Address 93603 0
235 Jones street
Building 10
Faculty of Health
University of Technology Sydney
Sydney NSW 2007
Country 93603 0
Australia
Phone 93603 0
+61295145971
Fax 93603 0
Email 93603 0
jane.maguire@uts.edu.au
Contact person for scientific queries
Name 93604 0
Jane Margaret Maguire
Address 93604 0
235 Jones street
Building 10
Faculty of Health
University of Technology Sydney
Sydney NSW 2007
Country 93604 0
Australia
Phone 93604 0
+61295145971
Fax 93604 0
Email 93604 0
jane.maguire@uts.edu.au

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 data point variables will be made available after completion of the study with appropriate ethical review board approvals and patient informed consent.
When will data be available (start and end dates)?
Start date January 2020
Finish Date December 2024
Data available December 2025
Available to whom?
To academic researchers with appropriate methodologically sound proposals and at the discretion of the Principal Investigators.
Available for what types of analyses?
Analyses such as meta-analysis and sub-studies that are in alignment with the aims of this study and the consent of the patients.
How or where can data be obtained?
Initial data access will be by request via email to lead study investigator jane.maguire@uts.edu.au. A data sharing committee of investigators and senior analyst will process requests for data and if approved, the RETHINK study analyst team will share the password protected data. Sharing will not include unrestricted access to the secure web based data repository.


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
No additional documents have been identified.