Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in IntraCranial Atherosclerotic diseaSe (CATIS- ICAS)

Prior treatment

• Symptomatic hemorrhagic transformation of the index stroke, or neuroradiological class 2 (PH2 type) or symptomatic class 3 on Heidelberg scale prior to randomization
• Previous non-traumatic intracerebral hemorrhage, non-aneurysmal subarachnoid hemorrhage (treated aneurysmal subarachnoid hemorrhage will be allowed)
• Subdural hematoma within 12 months prior to randomization or traumatic brain hemorrhage within 1 month prior to randomization
• Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) or P- glycoprotein (P-gp)
• Previous randomization to this study
• Participating in a study with an investigational drug or medical device that would interfere with the study at the time of randomization (participants that are no longer in an active arm of a study but are being followed may be randomized)

Other illness

• Cardioembolic stroke
• Indication for long-term dual antiplatelet or anticoagulant therapy (e.g. venous thromboembolism, coronary stent, mechanical prosthetic valve)
• Intracranial arterial stenosis secondary to causes other than atherosclerosis e.g. dissection, moya moya disease
• Substantial extracranial carotid artery disease ipsilateral to the qualifying stroke with plans for carotid revascularization
• Intended intracranial stenting for the qualifying stroke
• Uncontrolled hypertension with BP consistently above 180 mmHg for systolic and 110mmHg for diastolic while on treatment
• Known hypersensitivity or contraindication to ASA, clopidogrel or rivaroxaban
• Terminal medical illness with life expectancy less than 1 year

Lab values

• Advanced kidney disease at randomization (eGFR \<15 ml per minute)
• Platelet count less than 100,000/mm3 at enrolment or other bleeding diatheses

Other

• Females of childbearing potential who are not surgically sterile, pregnant, or breast-feeding

• Age \> 40 years
• Ischemic stroke or high-risk TIA (motor and/ or speech involvement)
• Randomization within 30 days of index stroke
• Stroke potentially attributable to ICAS 30-99% (or flow gap on time-offlight MRA) of a major intracranial artery (internal carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, intracranial vertebral artery, or basilar artery) by MRA or CTA or catheter angiography.
• Modified Rankin Scale Score \< 4 at randomization
• Ability to obtain informed consent prior to randomization.