*Prohibited con med list at bottom

Inclusion Criteria:

1. ≥40 years of age
2. AIS or TIA
   • Acute Ischemic Stroke: a neurological deficit attributable to an acute brain infarction and NIHSS score ≤ 7 and at least 1 of the following:
     • Persistent signs or symptoms of the ischemic event at the time of randomization, or
     • Acute, ischemic brain lesion determined by standard-of-care neuroimaging, or
     • Participant underwent thrombolysis or thrombectomy
   • Transient Ischemic Attack: acute onset neurological deficit attributable to focal ischemia of the brain by history or examination, with complete symptom resolution of the deficit and no brain infarction on neuroimaging (eg, CT scan or MRI, performed as part of standard medical practice), and ABCD2 Score ≥6
3. Randomization within 48 hours of onset of event
   • In participants in whom a stroke was evident on awakening from sleep, within 48 hours from the time at which the participants’ condition was last reported to be normal.
   • Participants who received thrombolysis and/or mechanical thrombectomy with or without stenting can be randomized but only after 24 hours have elapsed after the end of this treatment and not more than 48 hours after the onset of the index event, and provided that post-treatment neuroimaging excludes cerebral bleeding and have post-thrombolytic therapy/post-thrombectomy INR ≤ 1.5 and aPTT ≤ 1.4 times the ULN prior to study randomization.
   • Cerebrovascular vessel stenting is allowed as clinically indicated. If these procedures are done pre-randomization, then randomization should occur at least 24 hours after the end of the procedure and not more than 48 hours after the onset of the index event.
4. Current or planned antiplatelet treatment per international and/or local guidelines. If ASA is used, it will be limited to low dose (75 to 100 mg/day). Loading dose of antiplatelet agents (including ASA) are allowed per standard-of-care.
5. All female participants of childbearing potential must have a negative highly sensitive serum ( -human chorionic gonadotropin [ -hCG]) or urine test at screening
6. A female participant must agree not to be pregnant, breastfeeding, or planning to become pregnant until 4 days (5 half-lives) after the last dose of study intervention
7. A female participant must be (as defined in Appendix 5, Contraceptive and Barrier Guidance)
   • Not of childbearing potential, or
   • Of childbearing potential and practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method until 4 days (5 half-lives) after last dose of study intervention –the end of relevant exposure. The investigator must evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. Examples of highly effective methods of contraception are located in Appendix 5: Contraceptive and Barrier Guidance.
8. A female participant using hormonal contraceptives should use an additional non-hormonal contraceptive method (above that required in the inclusion criterion 7b) until 4 days after last dose (five half-lives) of study intervention –the end of relevant exposure
9. Participant must sign an ICF (or their legally authorized representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study and willing to provide at least vital status at the end of the study.
10. Willing and able to adhere to the lifestyle restrictions (Section 5.3) specified in this protocol.

Exclusion Criteria:

1. Current intracranial hemorrhage (hemorrhage into the brain, subarachnoid hemorrhage, intraventricular hemorrhage, subdural hematoma or epidural hematoma); except CMB and minor hemorrhagic transformation of infarct manifesting as scattered petechiae (Hemorrhagic Infarction Type 1 [HI1] according to Heidelberg classification).
   • Note: CMBs are defined as rounded foci of <10 mm in size that appear hypointense and are distinct from vascular flow voids, leptomeningeal hemosiderosis, or nonhemorrhagic subcortical mineralization on T2* weighted MRI.
2. Prior history of intracranial hemorrhage except subarachnoid hemorrhage > 1 year prior with adequate treatment.
3. The index stroke or TIA is considered to have a cardio-embolic etiology based on local standard-of-care investigations and for which guidelines recommend anticoagulation.
4. The index stroke or TIA considered to have another known cause, not related to athero-thrombotic sources (TOAST Other Determined Etiology) (Adams 1993), based on local standard-of-care investigations.
   • Examples of such etiologies include intracranial tumor, arteritis, arterial dissection, vasospasm or AVM.
5. Pre-event disability with mRS score of 3 or higher.
6. Any condition that requires chronic anticoagulation at the discretion of the investigator and/or local guidelines
   • Note: Participants with an indication for chronic antiplatelet therapy after placement of a bio-prosthetic nonmechanical valve (eg, transcatheter aortic valve replacement [TAVR]) do not satisfy this exclusion criterion and are eligible for study participation.
7. Conditions with an increased risk of bleeding, including:
   • Clinically significant bleeding within the previous 3 months
   • Known bleeding diathesis
   • Known aPTT prolongation > 1.4 times the ULN or known congenital FXI deficiency
   • Spinal cord hemorrhage
   • Retinal hemorrhage
8. Current active liver disease, eg, acute hepatitis, known cirrhosis, including participants receiving antiviral treatment for hepatitis.
9. History of any significant drug allergy (such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]).
10. Known allergies, hypersensitivity, or intolerance to milvexian or its excipients (refer to the milvexian IB).
11. Requires dialysis on a permanent basis.
12. eGFR <15 mL/min/1.73 m2 at screening.
13. Planned use of any disallowed therapies as noted in Section 6.8, Concomitant Therapy including isoniazid.
14. Received an investigational intervention or used an invasive investigational medical device within 4 weeks before the planned first dose of study intervention or is currently enrolled in an investigational interventional study.
15. Any of the following laboratory results, based on local laboratory, outside of the ranges specified below prior to randomization:
    • ALT 3X ULN
    • Platelet count <75,000 mm3
    • Total bilirubin ≥ 1.5x ULN unless an alternative causative factor such as Gilbert’s syndrome is identified
    • Hemoglobin <8.0 g/dL
16. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments or has a life expectancy of <12 months.
17. At the time of screening, any participant who will not consider following the study contact schedule, or not allow a contact to the participant, or to the designated family members or health care practitioner, to determine any endpoint events and/or vital status, up until the end of the study should they prematurely discontinue study intervention or withdraw from study participation.
18. Participants who are incarcerated, including prisoners or participants compulsorily detained for treatment of psychiatric disease.
19. Known current substance abuse that could impact study compliance
20. Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.

Note: Investigators must ensure that all study enrollment criteria have been met prior to
randomization. If a participant’s clinical status changes (including any available laboratory results
or receipt of additional medical records) after screening but before randomization such that the
participant no longer meets all eligibility criteria, then the participant must be excluded from
participation in the study.

Prohibited Concomitant Medications/Therapies:

1. Chronic (>4 weeks of consecutive use) use of ASA >100 mg per day.
2. Current or planned use of isoniazid.
3. Concomitant use of omeprazole or esomeprazole with clopidogrel is prohibited. Other use of PPI is allowed and encouraged. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.
4. Additional anticoagulants (eg, vitamin K antagonists, factor IIa or FXa inhibitors). The study intervention will be interrupted or discontinued in participants who develop any condition or procedure that requires open-label anticoagulant treatment. Study intervention may be resumed once anticoagulation is stopped.
5. Participants who received anticoagulants (eg, prophylactic dose UFH or LMWH) for DVT prophylaxis prior to randomization can be enrolled and a 3-day window of overlap with study intervention is allowed. The use of anticoagulants for post-stroke DVT prophylaxis after the 3-day window is prohibited and non-pharmacological prophylaxis (ie, intermittent pneumatic compression) is recommended. DVT prophylaxis with anticoagulants is prohibited after the initial hospitalization
6. The concomitant use of a combined P-gp and strong CYP3A4 inhibitor (eg, atazanavir, clarithromycin, itraconazole, ketoconazole, ritonavir, saquinavir) within 7 days of receiving study intervention and during the study is prohibited. Selection of an alternate concomitant medication with no or minimal P-gp/CYP3A4/5 inhibition is recommended.
7. The concomitant use of a combined P-gp and strong CYP3A4/5 inducer (eg, carbamazepine, phenytoin, rifampin) within 7 days of receiving study intervention and during the study is prohibited.