CLOPIDOGREL for Covert brain infarction

Inclusion criteria

• {"criterion_text":"- 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\t 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.\n- Life expectancy > 12 months\n- Predominantly independent in actives of daily living (mRS score ≤ 3)\n- Age ≥ 50 years"}

Exclusion criteria

• {"criterion_text":"- History of stroke/TIA\n- Breast-feeding\n- Patients with myopathy and/or elevated creatine kinase (CK) >5 × upper limit of normal (ULN)\n- 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.)\n- Patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir\n- Patients receiving a combination of sofosbuvir/velpatasvir/voxilaprevis\n- Patients receiving concomitant ciclosporin\n- Severe renal impairment (creatinine clearance <30 ml/min)\n- Hypersensitivity to the active substance or to any of the excipients\n- 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)\n- 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.)\n- 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.)\n- Co-existing progressive neurodegenerative disease including dementia or Parkinson’s disease.\n- Neoplastic condition that is uncontrolled or associated with an increased risk of bleeding\n- Patient already on antiplatelet or anticoagulation agent, regardless of indication\n- 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.\n- History of peptic ulcer disease or symptoms suggestive of active gastritis"}

Primary endpoints

• {"endpoint_text":"- Primary efficacy endpoint: MACCE. Primary safety endpoint: Fatal or major bleeding.","definition_or_measurement_approach":"Primary efficacy: MACCE (Major Adverse Cardiac and Cerebral Events) at 3 years. Primary safety: cumulative risk of major and fatal bleeding at 36 months. The 3-year MACCE endpoint will be blindly adjudicated by a clinical event committee."}

Secondary endpoints

• {"endpoint_text":"- Dementia (All-cause based on ICD-10 or ICD-11 diagnosis)\n- Cardiovascular Mortality\n- Cognitive Decline (MoCA-score)\n- Biomarkers of inflammation (Hs-CRP at baseline and correlated to the risk of future vascular events (MACCE), mortality (all-cause), and dementia (all-cause). )\n- The association between baseline physical activity levels, as measured by the International Physical Activity Questionnaire (IPAQ), and the incidence of MACCE at 36 months\n- 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.\n- 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.\n- 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.\n- 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.\n- 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).\n- 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\n- Ultrasonography (sub-study): The common- and internal carotid artery will be assessed for signs of atherosclerotic disease including plaques quantification.","definition_or_measurement_approach":"Dementia: diagnosis based on ICD-10 or ICD-11. Cognitive decline measured by MoCA score. Inflammation biomarkers: hs-CRP at baseline correlated with outcomes. Physical activity measured by IPAQ. mRS, CFS, BI and EQ-5D assessed at baseline, 12 and 36 months. MRI SVD score, GCA, Fazekas grade and cerebral microbleeds evaluated on baseline and 3-year MRI. Carotid plaque quantified by ultrasound in sub-study."}

Other endpoints

• {"endpoint_text":"- 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).\n- 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)\n- 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)\n- 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)\n- White matter lesion (WML) volume: To determine the difference in the growth of WML volume between baseline and 3-year MRI. (Imaging Sub-study)\n- Plaque quantification on ultrasound: To evaluate the association between carotid plaque quantification on ultrasound and the incidence of MACCE.(Imaging Sub-study)\n- 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)\n- MACCE: To evaluate the cumulative risk of MACCE at 5 and 10 years. (sub-study 5 and 10 years follow-up)\n- 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)\n- Dementia: To evaluate the incidence of all-cause dementia at 5 years and 10 years. (sub-study 5 and 10 years follow-up)\n- Cardiovascular Mortality: To evaluate the cumulative risk of cardiovascular-related mortality at 5 and 10 years. (sub-study 5 and 10 years follow-up)\n- 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)","definition_or_measurement_approach":"Stratified analyses defined by baseline systolic BP, LDL and hs-CRP thresholds. CBI subtype and infarct appearance classification based on MRI. Cognitive progression defined as ≥2-point reduction in MoCA. Imaging sub-studies use MRI-derived SVD score, WML volume, counts of new CBIs, ultrasound plaque quantification and pulsatility index. Long-term outcomes (5- and 10-year) assessed as cumulative incidence of MACCE, major/fatal bleeding, dementia, cardiovascular and all-cause mortality."}

Denmark

Earliest CTIS Part Ii Submission Date

25-09-2025

Latest Decision Or Authorization Date

17-10-2025

Processing Time Days

22

Number Of Sites

9

Number Of Participants

1102

Norway

Germany

Sweden

Primary sponsor

Full Name

Region Midtjylland

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Denmark

Third parties

• {"country":"Denmark","full_name":"Aarhus Universitet","duties_or_roles":"Sponsor duties codes: 1, 12","organisation_type":"Educational Institution"}