EUROpean pragmatic multicenter randomized trial on platelet inhibition and/or lipid lowering treatment in Covert Brain Infarction (CBI)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Region Midtjylland

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

18 Nov 2025 → ongoing

Decision date (initial)

2025-10-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Prophylaxis, Efficacy

Primary efficacy objective: To evaluate whether antiplatelet and/or statins in addition to risk factor management will provide a net long-term benefit in reducing vascular events and death (Major Adverse Cardiac and Cerebral Events (MACCE)) at 3 years in patients with covert brain infarctions.
Primary safety objective: To evaluate the cumulative risk of major and fatal bleeding at 36 months in patients with covert brain infarctions.

Secondary objectives 27

1. Dementia: To determine the incidence of all-cause dementia at 36 months.
2. Cardiovascular Mortality: To evaluate the cumulative risk of cardiovascular-related mortality at 36 months.
3. All-cause mortality: To evaluate the cumulative risk of all-cause mortality at 36 months.
4. Stroke (Ischemic and hemorrhagic): To evaluate the cumulative risk of stroke (ischemic and hemorrhagic) at 36 months.
5. Myocardial infarction (MI): To evaluate the cumulative risk of myocardial infarction (MI) at 36 months.
6. Cognitive Decline: To determine the proportion of participants experiencing significant cognitive decline, defined as a ≥2-point reduction in Montreal Cognitive Assessment (MoCA) scores at 36 months.
7. Adverse events: To determine the difference in the proportion of patients experiencing at least one serious adverse event (SAE) over 36 months.
8. Stratified MACCE: To determine the incidence of MACCE at 36 months, stratified by baseline systolic blood pressure (≥130 mmHg), low-density lipoprotein cholesterol (LDL) levels (≥1.4 mmol/L), and high-sensitivity C-reactive protein (hs-CRP >3 mg/L).
9. CBI subtype and infarct appearance: To evaluate the cumulative risk MACCE, mortality, and dementia at 36 months based on CBI subtype (lacunar vs. cortical) and infarct appearance (acute vs. chronic)
10. Cognitive Decline or Dementia Progression: To evaluate the risk of progression to all-cause dementia or significant cognitive decline (≥2-point reduction in MoCA scores) at 36 months, stratified by baseline systolic blood pressure (≥130 mmHg), LDL levels (≥1.4 mmol/L), and hs-CRP (>3 mg/L)
11. Cognitive function: To assess the difference in MoCA scores from baseline to respectively 12 and 36 months.
12. MRI Risk Markers: To determine the association between baseline MRI risk markers, quantified using the ordinal simplified SVD (small vessel disease) score correlated to the risk of MACCE, mortality, and dementia.
13. Inflammation Risk Markers: To evaluate the association between baseline hs-CRP levels and the risk of MACCE, mortality, and dementia.
14. Physical Activity and MACCE Risk: To determine the association between baseline physical activity levels and the incidence of MACCE at 36 months.
15. Functional status: To determine the change in the Modified Rankin Scale (mRS) score from baseline to respectively 12 and 36 months.
16. Frailty status: To determine the change in the Clinical Frailty Scale (CFS) score from baseline to respectively 12 and 36 months.
17. Functional independence in daily activities: To determine the change in the Barthel Index (BI) for Activities of Daily Living (ADL) score from baseline to respectively 12 and 36 months.
18. Quality of life: To determine the change in quality of life (EQ-5D) from baseline to respectively 12 and 36 months.
19. Progression of total SVD score: To determine the difference in progression of the total SVD score and the number of CBIs on follow-up MRI at 3 years (Imaging Sub-study))
20. White matter lesion (WML) volume: To determine the difference in the growth of WML volume between baseline and 3-year MRI. (Imaging Sub-study)
21. Plaque quantification on ultrasound: To evaluate the association between carotid plaque quantification on ultrasound and the incidence of MACCE.(Imaging Sub-study)
22. Pulsatility index on ultrasound: To evaluate the association between the middle cerebral artery pulsatility index on ultrasound and the risk of MACCE, mortality, and dementia.(Imaging Sub-study)
23. MACCE: To evaluate the cumulative risk of MACCE at 5 and 10 years. (sub-study 5 and 10 years follow-up)
24. Major bleeding and fatal bleeding: To evaluate the cumulative risk of major bleeding and fatal bleeding at 5 years and 10 years. (sub-study 5 and 10 years follow-up)
25. Dementia: To evaluate the incidence of all-cause dementia at 5 years and 10 years. (sub-study 5 and 10 years follow-up)
26. Cardiovascular Mortality: To evaluate the cumulative risk of cardiovascular-related mortality at 5 and 10 years. (sub-study 5 and 10 years follow-up)
27. All-cause mortality: To evaluate the cumulative risk of all-cause mortality at 5 and 10 years. (sub-study 5 and 10 years follow-up)

Conditions and MedDRA coding

Covert brain infarction (asymptomatic brain infarctions)

Study design 1 period

Regulatory references

Plan to share IPD

Yes

IPD plan description

The trial data will be uploaded to the CTIS database within one year after the end of study. Individual participant data underlying the baseline screening visit and 3 years outcome can be shared after de-identification, upon reasonable request and proposals should be directed at the study investigator. To gain access to these data, data requestors will need to sign a data processing agreement. Further, anonymized data will be available through public databases such as the Zenodo open data repository (CERN) or other equivalent databases after trial completion.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Deep/Lacunar infarct 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 Cortical infarct 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.
2. Life expectancy > 12 months
3. Predominantly independent in actives of daily living (mRS score ≤ 3)
4. Age ≥ 50 years

Exclusion criteria 17

1. History of stroke/TIA
2. 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)
3. 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.)
4. 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.)
5. Co-existing progressive neurodegenerative disease including dementia or Parkinson’s disease.
6. Neoplastic condition that is uncontrolled or associated with an increased risk of bleeding
7. Patient already on antiplatelet or anticoagulation agent, regardless of indication
8. Women of childbearing potential (WOCBP), defined as all women who have not undergone bilateral oophorectomy, hysterectomy, or medically confirmed ovarian failure, or who have not been postmenopausal for at least 12 consecutive months without an alternative medical cause, are excluded unless the following criteria are met: 1) A negative pregnancy test at baseline; and 2) Use of highly effective contraceptive measures throughout the study period.
9. History of peptic ulcer disease or symptoms suggestive of active gastritis
10. Breast-feeding
11. Patients with myopathy and/or elevated creatine kinase (CK) >5 × upper limit of normal (ULN)
12. A history of significant liver disease and/or excessive alcohol intake and/or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal (excessive alcohol intake defined as a history of alcohol-related liver dysfunction, including clinical signs such as ascites, spider naevi, caput medusae, or other stigmata of chronic liver disease.)
13. Patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir
14. Patients receiving a combination of sofosbuvir/velpatasvir/voxilaprevis
15. Patients receiving concomitant ciclosporin
16. Severe renal impairment (creatinine clearance <30 ml/min)
17. Hypersensitivity to the active substance or to any of the excipients

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary efficacy endpoint: MACCE. Primary safety endpoint: Fatal or major bleeding.

Secondary endpoints 12

1. Dementia (All-cause based on ICD-10 or ICD-11 diagnosis)
2. Cardiovascular Mortality
3. Cognitive Decline (MoCA-score)
4. Biomarkers of inflammation (Hs-CRP at baseline and correlated to the risk of future vascular events (MACCE), mortality (all-cause), and dementia (all-cause). )
5. The association between baseline physical activity levels, as measured by the International Physical Activity Questionnaire (IPAQ), and the incidence of MACCE at 36 months
6. mRS: The change in mRS score will be assessed from baseline to 12 and 36 months to evaluate shifts in functional independence and disability over time.
7. Clinical frailty scale: 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.
8. Barthel Index (BI): The change in BI score will be assessed from baseline to 12 and 36 months to evaluate the progression of functional independence in daily activities and overall disability status over time.
9. Quality of Life (EQ-5D): The change in EQ-5D score will be assessed from baseline to 12 and 36 months to evaluate variations in health-related quality of life over time.
10. MRI markers: At baseline the MRI SVD score will be estimated, and the score will be compared to the risk of future vascular events (MACCE), mortality (all-cause), and dementia (all-cause).
11. Repeated MRI after 3 years: Newly developed lacunar and/or cortical infarctions will be recorded and a SVD score, Global Cortical Atrophy (GCA) Scale, Fazekas grade and number of cerebral microbleeds will be calculated
12. Ultrasonography (sub-study): The common- and internal carotid artery will be assessed for signs of atherosclerotic disease including plaques quantification.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Region Midtjylland

Sponsor organisation

Region Midtjylland

Address

Palle Juul-Jensens Boulevard 99

City

Aarhus N

Postcode

8200

Country

Denmark

Scientific contact point

Organisation

Region Midtjylland

Contact name

Rolf A. Blauenfeldt

Public contact point

Organisation

Region Midtjylland

Contact name

Rolf A. Blauenfeldt

Third parties 1

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications