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Trial registered on ANZCTR


Registration number
ACTRN12623000949684
Ethics application status
Approved
Date submitted
2/08/2023
Date registered
4/09/2023
Date last updated
27/04/2025
Date data sharing statement initially provided
4/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating Cerebral micro-bleeding cHanges to Optimise anticoagulation thErapy in Stroke patients with Atrial Fibrillation
Scientific title
Evaluating Cerebral micro-bleeding cHanges to Optimise anticoagulation thErapy in Stroke patients with Atrial Fibrillation (ECHOES-AF) Pilot trial
Secondary ID [1] 310268 0
Nil known
Universal Trial Number (UTN)
U1111-1295-9976
Trial acronym
ECHOES-AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial fibrillation (AF) 330956 0
Anticoagulant therapy 330957 0
Silent brain infarct (SBI) 330958 0
Cerebral microbleed (CMB) 330959 0
Cerebral small vessel disease (CSVD) 330960 0
Condition category
Condition code
Cardiovascular 327759 327759 0 0
Diseases of the vasculature and circulation including the lymphatic system
Stroke 327760 327760 0 0
Haemorrhagic
Stroke 327761 327761 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Before enrolment, participants will go through the 2-steps screening process: first, the site research clinician will confirm whether the participant is eligible to participate in the trial as per the inclusion/exclusion criteria. For participants with unknown CMB status but with WMH (the Fazekas WMH scale score =1 for either periventricular or subcortical WMHs) or old vascular lesions (lacune, prior ischemia or bleeding) on brain CT or MRI obtained in the stroke acute phase and being eligible for MRI screening, they will have a brain MRI examination that takes around 20 minutes at the participating site (if a 3.0 Tesla MRI machine is available) or at other designated MRI centres. The MRI will be performed pre-randomisation (Screening Part 2, if no confirmed CMB on MRI pre-screening), and then at 12 month (end of study). All the raw MRI images will be uploaded to the central imaging database after a de-identification of the participant personnel information. Central investigators will double-check the CMB presence on the uploaded MRI and use it as a baseline reference for assessing CMB and other CSVD progressions on the 1-year brain MRI. The site clinician will notify the participant about the MRI examination result. For participants with known CMB presence on brain MRI performed in the stroke acute phase and corresponding radiology report can be provided, the brain MRI examination will be waived.
Participants then will be randomised at a 1:1 ratio to have a lower-dose Non-Vitamin-K-antagonist Oral Anticoagulant (NOAC) treatment or a guideline-recommended anticoagulation therapy by standard-dose NOAC, with stratifications by age (< or =75 years), sex (male or female), CMB burden (< or =5 CMBs), and the sequential phases of AF detection (before/in hospitalisation due to stroke or after discharge).
Intervention: lower-dose dabigatran (110 mg, oral capsule, twice daily) or rivaroxaban (15 mg, oral tablet, once daily) or apixaban (2.5 mg, oral tablet, twice daily) or edoxaban (30 mg, oral tablet, once daily) for 12 months (edoxaban will not be applied to participants recruited in Australia). The selection of NOAC will depend on the drug availability at each site and the site clinician’s discretion.
The participant shall record the daily use of OAC in a dedicated form provided by the study team. At each clinic visit during follow-up, the clinical specialist will collect the form and give it to the research team.
Intervention code [1] 326649 0
Prevention
Intervention code [2] 326650 0
Treatment: Other
Intervention code [3] 326806 0
Treatment: Drugs
Comparator / control treatment
Before enrolment, participants will go through the 2-steps screening process: first, the site research clinician will confirm whether the participant is eligible to participate in the trial as per the inclusion/exclusion criteria. For participants with unknown CMB status but with WMH (the Fazekas WMH scale score =1 for either periventricular or subcortical WMHs) or old vascular lesions (lacune, prior ischemia or bleeding) on brain CT or MRI obtained in the stroke acute phase and being eligible for MRI screening, they will have a brain MRI examination that takes around 20 minutes at the participating site (if a 3.0 Tesla MRI machine is available) or at other designated MRI centres. The MRI will be performed pre-randomisation (Screening Part 2, if no confirmed CMB on MRI pre-screening), and then at 12 month (end of study). All the raw MRI images will be uploaded to the central imaging database after a de-identification of the participant personnel information. Central investigators will double-check the CMB presence on the uploaded MRI and use it as a baseline reference for assessing CMB and other CSVD progressions on the 1-year brain MRI. The site clinician will notify the participant about the MRI examination result. For participants with known CMB presence on brain MRI performed in the stroke acute phase and corresponding radiology report can be provided, the brain MRI examination will be waived.
Participants then will be randomised at a 1:1 ratio to have a lower-dose Non-Vitamin-K-antagonist Oral Anticoagulant (NOAC) treatment or a guideline-recommended anticoagulation therapy by standard-dose NOAC, with stratifications by age (< or =75 years), sex (male or female), CMB burden (< or =5 CMBs), and the sequential phases of AF detection (before/in hospitalisation due to stroke or after discharge).
Participants assigned to the control group will receive standard-dose dabigatran (150 mg, oral capsule, twice daily) or rivaroxaban (20 mg, oral tablet, once daily) or apixaban (5 mg, oral tablet, twice daily) or edoxaban (60 mg, oral tablet, once daily) for 12 months (edoxaban will not be applied to participants recruited in Australia).
The participant shall record the daily use of OAC in a dedicated form provided by the study team. At each clinic visit during follow-up, the clinical specialist will collect the form and give it to the research team.
Control group
Active

Outcomes
Primary outcome [1] 341235 0
All-cause mortality
Timepoint [1] 341235 0
One year after randomisation
Secondary outcome [1] 424962 0
Major bleeding events, intracranial haemorrhage (ICH), and any bleeding – to be other safety outcomes of interest. Method of assessment: AESI/SAE forms.
Timepoint [1] 424962 0
One year after randomisation
Secondary outcome [2] 424963 0
Participant retention and NOAC adherence – the rate of enrolled participants being retained in the trial and the rate of those with good adherence to NOAC (proportion of days covered for NOAC use within the past 2 weeks =80%) at 1-year post-randomisation.
Timepoint [2] 424963 0
One year after randomisation
Secondary outcome [3] 446867 0
Efficacy – to assess whether there are any differences in the effectiveness of lower-dose NOAC versus standard-dose NOAC on a composite of thromboembolism-related outcomes (including recurrent stroke/TIA, myocardial infarction, extracranial systemic embolism, cognitive impairment or dementia, and severe neurological disability) and its components.
Timepoint [3] 446867 0
One year after randomization

Eligibility
Key inclusion criteria
1. Adults (age greater than or equal to 18 and less than 85 years) with ischaemic stroke or TIA within the past 6 months (more than 1 week after stroke onset) and clinically stable*.
2. With known or newly diagnosed non-valvular AF or AFL (AF/AFL in the absence of moderate-to-severe mitral stenosis or a mechanical heart valve) based on electrocardiography (ECG) (12-lead ECG, rhythm strip, or Holter), medical records, and/or cardiac imaging examination.
3. Take NOAC at the trial entry or be willing to receive NOAC for thromboprophylaxis without any contradiction, and standard-dose NOAC is applicable.
4. With more than or equal to 1 CMB detected on brain magnetic resonance imaging (MRI) examination.
5. Non-severe neurological disability (mRS score less than or equal to 3).
6. Capacity to give consent themselves.
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of heart valve disease due to moderate-to-severe mitral stenosis or with a mechanical heart valve.
2. AF/AFL due to reverse causes of cardiac surgery, pulmonary embolism, and untreated hyperthyroidism.
3. Known presence of atrial myxoma, left ventricular thrombus, or active endocarditis.
4. Other significant active neurological illnesses present since suffering a stroke (e.g., recurrent seizures*, multiple sclerosis, brain tumour). Well-controlled epilepsy present prior to the stroke, a single seizure at the stroke onset or provoked seizure is not an exclusion.
*Note that recurrent seizure(s) are defined as = 2 seizures that are unprovoked (i.e., not related to reversible stressors) and that occur >24 hours apart in the past three months.
5. Known or detecting competing brain lesions associated with ICH predisposition except cortical superficial siderosis on brain MRI, such as neoplasm, arteriovenous malformation, cavernous hemangioma, aneurysm, and subdural haematoma.
6. Has been diagnosed as having dementia on formal clinical assessment.
7. Diagnosis of hypotension, defined as sitting systolic blood pressure less than 100 mmHg.
8. Currently taking warfarin but cannot/unwilling to be switched to a NOAC.
9. Unable to swallow tablets/capsules.
10. Major cardiac surgery or transcatheter intervention within the past 2 months or planned cardiac surgery or transcatheter intervention within the next 3 months.
11. Have malignancy or other serious concomitant diseases with a life expectancy of 3x upper limit of the normal range [ULN], acute clinical hepatitis, chronic active hepatitis, or cirrhosis).
15. Any other conditions associated with increased bleeding risks:
• Major non-cardiac surgery within the past 2 months or planned non-cardiac surgery within the next 3 months.
• Anaemia (haemoglobin level 100 mmHg).
• Needs anticoagulant therapy for disorders other than AF.
16. Any other condition, in the opinion of investigators, that renders the patient unsuitable for the trial (such as clinically significant out of the normal range of serum sodium [145 mmol/L] or potassium [5.5 mmol/L]) and would compromise adherence, safe participation, and follow-up in the trial (e.g., drug addiction, alcohol abuse, history of drug overdose or attempted suicide or significant active mental illness, moving outside or visitor to the area, etc.).
17. Have other definite contradictions for NOAC (e.g., concomitant use of prohibited medications [please see 7.5.2]) and or definite indications for lower-dose NOAC (e.g., concomitant use of restricted medications).

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 (database)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratifications by age (< or =75 years), sex (male or female), CMB burden (< or =5 CMBs), and the sequential phases of AF detection (before/in hospitalisation due to stroke or after discharge).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Simple descriptive statistics and tests (proportions, means, chi-squared, t-tests) will be used to describe differences in baseline characteristics, 1-year participant retention and NOAC adherence rates between two randomised groups. Kaplan-Meier curves and Cox proportional regression models will be used to analyse time-to-event outcomes of any death and major bleeding events (safety analysis). Binary logistic regression models will be used to show the effectiveness of (off-label) lower-dose NOAC on anticoagulation efficacy outcomes and SAEs. For those completing 1-year brain MRI, proportions of those with CMB and other CSVD progressions will be compared between the two randomised groups with adjustments of key clinical covariates.
A sample size of 200 participants is proposed according to the existing clinical resource (i.e., clinic sites where Principle Investigators and other trial collaborators are affiliated), the amount of grant support, a comprehensive systematic review on the prevalence of CMB in people with AF conducted by the trial team,30 an estimation of 1-year event rate of the primary outcome in the target population on standard-dose NOAC treatment, and a strategy adopted in the LACI-2 (Lacunar Intervention Trial-2) trial, a similar Phase II preparatory to Phase III trial that evaluated the trial feasibility, participant retention, adherence/safety/tolerability to isosorbide mononitrate and cilostazol, and effects of the two drugs on common clinical outcomes in patients with lacunar ischaemic stroke.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2025
Actual
Date of last participant enrolment
Anticipated
1/12/2026
Actual
Date of last data collection
Anticipated
1/12/2027
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 27842 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 44037 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 314475 0
Government body
Name [1] 314475 0
The NSW Cardiovascular Elite Postdoctoral Researcher Grant
Country [1] 314475 0
Australia
Funding source category [2] 314618 0
Other Collaborative groups
Name [2] 314618 0
The George Institute for Global Health
Country [2] 314618 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The George Institute for Global Health
Address
Level 5, 1 King St, Newtown, NSW 2042
Country
Australia
Secondary sponsor category [1] 316580 0
None
Name [1] 316580 0
Address [1] 316580 0
Country [1] 316580 0
Other collaborator category [1] 282773 0
University
Name [1] 282773 0
University of Edinburgh
Address [1] 282773 0
5 Forrest Hill, Edinburgh EH1 2LX, UK
Country [1] 282773 0
United Kingdom
Other collaborator category [2] 282774 0
Hospital
Name [2] 282774 0
Shanghai Ren Ji Hospital
Address [2] 282774 0
No. 160 Pujian Road, Pudong New District, Shanghai, 200127
Country [2] 282774 0
China
Other collaborator category [3] 282775 0
Hospital
Name [3] 282775 0
Beijing Anzhen Hospital
Address [3] 282775 0
No. 2 Anding Road, Chaoyang District, Beijing, 100029
Country [3] 282775 0
China

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313526 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 313526 0
Ethics committee country [1] 313526 0
Australia
Date submitted for ethics approval [1] 313526 0
26/06/2024
Approval date [1] 313526 0
30/09/2024
Ethics approval number [1] 313526 0
X24-0203 & 2024/ETH01322

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

Contacts
Principal investigator
Name 128450 0
Dr Zien Zhou
Address 128450 0
The George Institute for Global Health (Level 5, 1 King St, Newtown, NSW 2042)
Country 128450 0
Australia
Phone 128450 0
+61 434432202
Fax 128450 0
Email 128450 0
[email protected]
Contact person for public queries
Name 128451 0
Craig Anderson
Address 128451 0
The George Institute for Global Health (Level 5, 1 King St, Newtown, NSW 2042)
Country 128451 0
Australia
Phone 128451 0
+61280524521
Fax 128451 0
+61280524502
Email 128451 0
[email protected]
Contact person for scientific queries
Name 128452 0
Zien Zhou
Address 128452 0
The George Institute for Global Health (Level 5, 1 King St, Newtown, NSW 2042)
Country 128452 0
Australia
Phone 128452 0
+61 434432202
Fax 128452 0
Email 128452 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers who provide a methodologically sound proposal and whose proposed use of the data has been approved by the study office identified for this purpose.

Conditions for requesting access:
• -

What individual participant data might be shared?
• Individual participant data underlying published results after deidentification (text, tables, figures, and appendices).

What types of analyses could be done with individual participant data?
• To achieve aims in the approved proposal or for individual participant data meta-analysis..

When can requests for individual participant data be made (start and end dates)?
From:
Beginning 3 months following main results publication with no end date determined.

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?
• Access subject to approvals by Principal Investigator ([email protected]). To gain access, data requestors will need to sign a data access agreement.

Are there extra considerations when requesting access to individual participant data?
No


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.