CATIS-ICAS is a double-blind, randomized, placebo-controlled (RCT), phase III study seeking to demonstrate that oral rivaroxaban 2.5 mg twice daily plus aspirin daily is superior to clopidogrel 75 mg daily plus aspirin daily for 90 days followed by placebo plus aspirin daily for preventing recurrent stroke in those with ischemic stroke secondary to intracranial atherosclerotic disease (ICAD) of 30-99%, when started within 30 days of index stroke.

CATIS-ICAD will recruit approximately 1172 consenting participants presenting with ischemic stroke secondary to ICAD within 30 days from symptom onset at approximately 80 high-volume stroke research centers across Canada, Europe, South America and Asia over 48 months. Participants will be randomly assigned (1:1) to oral intake of rivaroxaban 2.5 mg twice daily plus aspirin or clopidogrel 75 mg daily plus aspirin followed by aspirin plus placebo. They will be followed to a common termination date, defined as approximately 12 months following the end of recruitment (estimated mean follow-up of 36 months).

Inclusion Criteria:

1. Age > 40 years
2. Ischemic stroke or high-risk TIA (motor and/ or speech involvement)
3. Randomization within 30 days of index stroke
4. 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.
5. Modified Rankin Scale Score < 4 at randomization
6. Ability to obtain informed consent prior to randomization.

Exclusion Criteria:

1. Cardioembolic stroke
2. Indication for long-term dual antiplatelet or anticoagulant therapy (e.g. venous thromboembolism, coronary stent, mechanical prosthetic valve)
3. Intracranial arterial stenosis secondary to causes other than atherosclerosis e.g. dissection, moya moya disease
4. Substantial extracranial carotid artery disease ipsilateral to the qualifying stroke with plans for carotid revascularization
5. Intended intracranial stenting for the qualifying stroke
6. Symptomatic hemorrhagic transformation of the index stroke, or neuroradiological class 2 (PH2 type) or symptomatic class 3 on Heidelberg scale prior to randomization
7. Previous non-traumatic intracerebral hemorrhage, non-aneurysmal subarachnoid hemorrhage (treated aneurysmal subarachnoid hemorrhage will be allowed)
8. Subdural hematoma within 12 months prior to randomization or traumatic brain hemorrhage within 1 month prior to randomization
9. Advanced kidney disease at randomization (eGFR <15 ml per minute)
10. Platelet count less than 100,000/mm3 at enrolment or other bleeding diatheses
11. Uncontrolled hypertension with BP consistently above 180 mmHg for systolic and 110mmHg for diastolic while on treatment
12. Known hypersensitivity or contraindication to ASA, clopidogrel or rivaroxaban
13. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) or P- glycoprotein (P-gp)
14. Females of childbearing potential who are not surgically sterile, pregnant, or breast-feeding
15. Previous randomization to this study
16. 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)
17. Terminal medical illness with life expectancy less than 1 year