A EUROpean Randomized Study on Blood-thinners and Cholesterol-lowering Treatments to Prevent Future Vascular Events in People With Covert Brain Infarcts (CBI)

Phase 3

Not yet recruiting

• Conditions: Covert Brain Infarction
• Interventions: Drug: acetylsalicyclic acid (ASA); Drug: Rosuvastatin; Drug: Clopidogrel; Drug: Atorvastatin

• Registration Number: NCT07012629
• Lead Sponsor: Aarhus University Hospital

Brief Summary

Magnetic resonance imaging (MRI) is commonly used in healthcare, and sometimes it shows small areas of brain damage called Covert Brain Infarcts (CBIs). These are usually found by chance when people have scans for things like headaches or dizziness. Although CBIs don't cause symptoms at the time, they are linked to a higher risk of future stroke and death.

There is currently no standard treatment for CBIs, and doctors have different approaches-some give stroke-preventing medication (like antiplatelets or statins), while others don't treat at all. This is mostly because there isn't enough research yet.

This study will test whether stroke-preventing treatments help people with CBIs. It will also look at whether having a CBI increases the risk of dementia, and whether treatment might lower that risk.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-06
• Study First Submitted: 2025-06-01
• Study First Submitted QC: 2025-06-01
• Last Update Submitted: 2025-06-01
• Study First Posted: 2025-06-10
• Last Update Posted: 2025-06-10
• Study Start: 2025-09-01
• Primary Completion: 2031-09-30
• Study Completion: 2040-01-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1652

Inclusion Criteria

• MRI demonstrating a lacunar infarct (acute/subacute/chronic) without prior stroke/TIA symptoms. (A round or ovoid, subcortical, fluid-filled cavity (signal similar to cerebrospinal fluid (CSF)) between 3 and 15 mm in diameter and demonstrating a peripheral T2/FLAIR hyperintense rim of marginal gliosis. For infratentorial lesions the hyperintense rim may be less marked and a complete ring is not required) OR
• MRI demonstrating a cortical infarct (acute/subacute/chronic) without prior stroke/TIA symptoms (A cortical infarct is defined as a fluid-filled cavity (signal similar to CSF) in the cortex, juxtacortical region or cerebellar cortex and with a ring of T2/FLAIR hyperintense lesions or as cortical T2/FLAIR lesions without a fluid-filled cavity with presumed vascular origin. Both supra- and infratentorial lesion will be included) AND Life expectancy > 12 months AND Predominantly independent in actives of daily living (mRS score ≤ 3) AND Age ≥ 50 years

Exclusion Criteria

• History of stroke/TIA
• High risk of bleeding (e.g., recent or recurrent gastrointestinal or genitourinary bleeding associated with a decrease in hemoglobin levels of at least 1 mmol/L, active peptic ulcer disease, MRI with cortical siderosis and/or prior lobar hemorrhage)
• Indication for long-term use of anticoagulants (e.g. deep vein thrombosis, pulmonary embolism, atrial fibrillation, and rarer indications; such as mechanical heart valve, antiphospholipid antibody syndrome etc.)
• Concurrent indication for lipid-lowering treatment and/or platelet-inhibitors for secondary cardiovascular prevention (ischemic heart disease, recent stenting, ischemic stroke, revascularization surgeries, lower-extremity atherosclerotic arterial disease etc.)
• Co-existing progressive neurodegenerative disease including dementia or Parkinson's disease.
• Neoplastic condition that is uncontrolled or associated with an increased risk of bleeding
• Patient already on antiplatelet or anticoagulation agent, regardless of indication
• Women with a history of menopause below 12 months are only included after negative pregnancy test

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Group A: Platelet inhibitor - no Statin ("APT alone")	acetylsalicyclic acid (ASA)	All patients will initiate treatment with Aspirin or Clopidogrel. The decision on which of the two drugs to initiate is at the discretion of the treating physician/center.
Group A: Platelet inhibitor - no Statin ("APT alone")	Clopidogrel	All patients will initiate treatment with Aspirin or Clopidogrel. The decision on which of the two drugs to initiate is at the discretion of the treating physician/center.
Group B: Statins - no Platelet inhibitor ("Statin alone").	Rosuvastatin	Patients will be treated with high-intensity statin therapy (Atorvastatin 40 mg once daily or Rosuvastatin 20 mg once daily)
Group B: Statins - no Platelet inhibitor ("Statin alone").	Atorvastatin	Patients will be treated with high-intensity statin therapy (Atorvastatin 40 mg once daily or Rosuvastatin 20 mg once daily)
Group C: Statins - Platelet inhibitor ("APT AND statin")	acetylsalicyclic acid (ASA)	Both types of medication are initiated as described in group A and B
Group C: Statins - Platelet inhibitor ("APT AND statin")	Clopidogrel	Both types of medication are initiated as described in group A and B
Group C: Statins - Platelet inhibitor ("APT AND statin")	Rosuvastatin	Both types of medication are initiated as described in group A and B
Group C: Statins - Platelet inhibitor ("APT AND statin")	Atorvastatin	Both types of medication are initiated as described in group A and B

Primary Outcome Measures

Name	Time	Method
Major Adverse Cardiac and Cerebral Events (MACCE) at 12 and 36 months	12 months and 36 months post-randomization.	MACCE are defined as the occurrence of any of the following events; * All cause death: Death from any cause; * Acute myocardial infarction: Admission with a discharge diagnosis of ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) and; * Stroke: AIS\* or Intracerebral hemorrhage (non-traumatic) \*Including Transient Ischemic Attack (TIA) with evidence of brain tissue infarction i.e. remission of symptoms within 24 hours but who have an acute ischemic lesion on diffusion weighted imaging MRI.; All events qualifying for a MACCE event will be adjudicated by the Clinical event committee.; Accepted timeframe for evaluation is +/- 30 days
Major and fatal bleeding at 12 and 36 months	12 months and 36 months post-randomization.	Major and fatal bleeding events are defined according to criteria established by the International Society on Thrombosis and Haemostasis (ISTH): * Fatal bleeding, and/or; * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or; * Bleeding leading to a drop in hemoglobin of ≥20 g/L (1.24 mmol/L), or requiring transfusion of two or more units of whole blood or red cells.; All qualifying events will be adjudicated by an independent Clinical Event Committee (CEC).; The accepted time window for assessment is ±30 days.

Secondary Outcome Measures

Name	Time	Method
All-cause dementia	12 months and 36 months post-randomization.	Dementia is identified through phone contact and review of the patient's electronic health record, based on national diagnostic standards. Accepted diagnoses align with ICD-10 and ICD-11. ICD-10 codes include: dementia in Alzheimer's disease (F00.0-F00.9, DG30.0-DG30.9), vascular dementia (F01.0-F01.9, F00.2), dementia in other diseases classified elsewhere (F02.0-F02.8), unspecified dementia (F03.9), Lewy body dementia (DG31.8E), progressive isolated aphasia (DG31.0A), Pick disease (DG31.0B), and unspecified degenerative disease of the nervous system (DG31.9). ICD-11 codes include: dementia due to Alzheimer's disease (6D80), cerebrovascular disease (6D81), Lewy body disease (6D82), frontotemporal dementia (6D83), other specified diseases (6D85.Y), and dementia of unknown or unspecified cause (6D8Z). The accepted time window for evaluation is ±30 days.
Cardiovascular-related mortality	12 months and 36 months post-randomization.	Information about cardiovascular mortality is collected from telephone contacts and from the patient's electronic health record. See the table below for the definition of cardiovascular mortality.; Cardiovascular Mortality are defined as: * Acute MI; * Sudden cardiac death; * Heart failure; * Stroke: death as a direct consequence or complication of stroke; * Cardiovascular procedure; * Cardiovascular-related haemorrhage: non-stroke intracranial haemorrhage (subdural hematoma), non-procedural or non-traumatic vascular rupture (e.g. aortic aneurysm), or haemorrhage causing cardiac tamponade; * Death due to other cardiovascular causes: a cardiovascular death not included in the above categories but with a specific, known cause (e.g., pulmonary embolism or peripheral arterial disease); Accepted time for evaluation is +/- 30 days
Cognitive decline	After 12 months and a end of treatment at 36 months	A significant cognitive decline, defined as a ≥2-point reduction in Montreal Cognitive Assessment (MoCA) scores at 36 months.; The participant's score on the full 12 item in-person MoCA (30 points) at the initial visit is compared to the scores on the telephone administrated Tele-MoCA (items from MoCA not requiring the use of a pencil and paper or visual stimulus, maximum of 22 points) after 12 and 36 months.; Accepted time for evaluation is +/- 30 days
Serious adverse event (SAE)	From enrollment to the end of treatment at 36 months	Information on SAEs will be reported by the investigators and recorded in the eCRF.
Baseline MRI risk markers, quantified using the ordinal simplified SVD-score (small vessel disease) score	After 12 months and at the end of treatment at 36 months	Simple SVD defined as score: Microbleeds: 0 microbleeds = 0 point; ≥ 1 microbleed = 1 point White matter hyperintensities (Fazekas): Fazekas 0-1 = 0 point; Fazekas 2-3 = 1 point. Lacunes: 0-2 lacunes = 0 point; \>2 lacunes = 1 point. Total SVD score (range): 0-3.
Physical activity levels	At baseline	Baseline physical activity levels are measured by the International Physical Activity Questionnaire (IPAQ).It yields a categorical score: low, moderate, or high level of physical activity. The follow-up assessment will be performed by staff from the enrolling site.; Accepted time for evaluation is +/- 30 days
Modified Rankin Scale (mRS) score	From baseline to 12 months and to the end of treatment at 36 months	The change in mRS score will be assessed to evaluate shifts in functional independence and disability over time. The mRS ranges from 0 to 6, with higher scores indicating worse outcomes. The follow-up assessment at 12 and 36 months will be performed by staff from the enrolling site.; Accepted time for evaluation is +/- 30 days
Clinical Frailty Scale (CFS) score	From baseline to 12 months and to the end of treatment at 36 months	The change in CFS score will be assessed from baseline to 12 and 36 months to evaluate the progression of frailty and its impact on functional status and overall health over time. It ranges from 1 to 9, with 1 indicating "very fit" and 9 indicating "terminally ill." The follow-up assessments at 12 and 36 months will be performed by staff from the enrolling site Accepted time for evaluation is +/- 30 days
Barthel Index (BI) for Activities of Daily Living (ADL)	From enrollment to 12 months and to the end of treatment at 36 months	The Barthel Index is a score that describes the degree of independence in relation to assistance from another person. It ranges from 0 to 100, with higher scores indicating greater independence. A score close to 100 reflects that the individual is self-sufficient, whereas lower scores indicate increasing dependence on others in daily activities. A score near 0 typically suggests that the individual is bedridden and requires help with all tasks.; The follow-up assessments at 12 and 36 months will be performed by staff from the enrolling site.; Accepted time for evaluation is +/- 30 days
Quality of life (EQ-5D)	From enrollment to 12 months and to the end of treatment at 36 months	The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.; The follow-up assessments at 12 and 36 months will be performed by staff from the enrolling site.; Accepted time for evaluation is +/- 30 days
CBI subtype	At baseline	The CBI subtype and infarct appearance will be described by the enrolling physician, who has been trained to identify these findings on MRI.; The baseline MRI will be visually graded by the investigators and the total SVD score calculated.; The DICOM (Digital Imaging and Communications in Medicine) file containing the MRI will be downloaded and uploaded to the electronic case report form (eCRF) at redcap.au.dk, for later assessment by an imaging core lab.

Trial Locations

Locations (14)

Aalborg Universitetshospital; 🇩🇰 Aalborg, Denmark

Aarhus Universitetshospital; 🇩🇰 Aarhus, Denmark

Aarhus University Hospital; 🇩🇰 Aarhus, Denmark

Herlev Hospital; 🇩🇰 Herlev, Denmark

Regionshospitalet Gødstrup; 🇩🇰 Herning, Denmark

Kolding Hospital; 🇩🇰 Kolding, Denmark

Rigshospitalet; 🇩🇰 København, Denmark

Bispebjerg og Frederiksberg Hospital; 🇩🇰 København, Denmark

Odense Universitetshospital; 🇩🇰 Odense, Denmark

Roskilde Hospital; 🇩🇰 Roskilde, Denmark

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