Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized, Double-blind, Evaluation in Secondary Stroke Prevention Comparing the EfficaCy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate (110 mg or 150 mg, Oral b.i.d.) Versus Acetylsalicylic Acid (100 mg Oral q.d.) in Patients With Embolic Stroke of Undetermined Source (RESPECT ESUS)
Brief Summary: This trial will enroll approximately 6,000 patients with recent embolic stroke of unknown source (ESUS). Patients will be randomized to dabigatran or acetylsalicyclic acid (ASA) (1:1 ratio) and have visits every three months. The study doctor may prescribe blinded concomitant ASA for pts with coronary artery disease but this is not mandatory. All Adverse Events (AEs), Serious Adverse Events (SAEs), outcome events will be recorded. The trial will conclude when the required number of stroke events are positively adjudicated which is estimated to take 3 years (including 2.5 years of enrollment).


Options:
A: Inclusion Criteria:

1. Signed Written Informed Consent
2. Males and Females over 18 years of age.
3. History of Nonvalvular Atrial Fibrillation (NVAF) by documentation in the medical history or newly diagnosed nonvalvular Atrial Fibrillation at time of study randomization by ECG, device or telemetry .
4. Diagnosis of TIA or small or medium ischemic stroke 0 to 48 hours from signs or symptoms.
5. Women of child-bearing potential must use a reliable method of contraception and must provide a negative pregnancy test at entry into the study and within 24 hours of study treatment initiation.
6. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug Apixaban plus 5 half-lives (approximately 3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post-treatment completion.
7. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with Apixaban plus 5 half-lives (approximately 3 days) plus 90 days (duration of sperm turnover) for a total of 93 days post-treatment completion.
8. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.

Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of \< 1% when used consistently and correctly.

At a minimum, subjects must agree to the use of one method of highly effective contraception as listed below:

HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

* Male condoms with spermicide
* Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug
* IUDs, such as ParaGard™
* Tubal ligation
* Vasectomy.
* Complete Abstinence

Exclusion Criteria:

1. Hemorrhagic stroke
2. Large ischemic stroke
3. History of major bleeding within the last 6 months from time of subject enrollment (e.g. GI bleed).
4. History of intracranial bleed

   a. Traumatic intracranial bleed within one year of randomization. (Traumatic ICH greater than one year of randomization is not an exclusion).
5. Current or history of bleeding disorders (e.g. blood dycrasias)
6. Blood Pressure of 180/100 mmHg on hypertensive therapy day of randomization per PI discretion 20.
7. Current illicit drug use and/or chronic alcohol use per PI discretion.
8. Severe liver disease (AST/ALT 2x upper limit).
9. Patients with kidney disease meeting criteria to take 2.5 mg twice daily who are taking strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin) .
10. Any other suspected etiology for stroke (e.g. ipsilateral carotid disease).
11. Greater than 3 Cerebral Micro-bleeds (CMB) on gradient recovery echo (GRE) or evidence of intracranial hemorrhage on CT at time of randomization. (SWI sequencing may be used if GRE sequencing is not obtainable)
12. Therapeutically anti-coagulated at time of admission (INR at admission greater than 2.0 on warfarin or took two consecutive doses of NOAC).
13. Absolute indication for use of warfarin only.( e.g. Mechanical Valve)
14. Absolute indication for anticoagulation prior to randomization window. (e.g. DVT)
15. Hemoglobin less than 9 gm/dl and/or platelet count less than 100 K/uL.
16. Requires dual antiplatelet therapy.
17. Daily use of NSAIDS
18. Pregnancy or lactation.
19. Any use of an investigational product within the past 30 days.
20. Prisoners or subjects who are involuntarily incarcerated.
21. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
22. Concurrent participation in another clinical study where use of an investigational product is used
B: Inclusion Criteria:

* Disabling Ischemic stroke symptoms with onset \< 3 hours treated with IV rt-PA by local standards\*.

  \* or ≤ 4.5 hours according to local standard of care.
* NIHSS ≥ 10\* or any NIHSS with an intracranial clot should be demonstrated on neurovascular imaging (TCD or CTA) in any one of the following areas: distal internal carotid artery (ICA) carotid artery (CA), middle cerebral artery (MCA - M1 or M2), posterior cerebral artery (PCA - P1 or P2), distal vertebral or basilar artery.
* TCD criteria: Thrombolysis in brain ischemia (TIBI) 0, 1, 2 or 3 - CT-Angiogram: thrombolysis in myocardial ischemia (TIMI) 0 or 1 \* NIHSS ≥ 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with non-contrast head CT alone), but if performed, a clot must be demonstrated.
* For those patients who will undergo repeat CT-Angiogram at 2-3 hours, estimated glomerular filtration rate (eGFR) must be ≥ 60 mL/min/1.73m2.
* Females of childbearing potential must have a negative serum pregnancy test (HCG) prior to the administration of trial medication.
* Signed (written) informed consent by the patient or the patient's legal representative and/or guardian.

Exclusion Criteria:

* Patients whom the treating physician is planning (or could plan) to treat with intra-arterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalization.
* Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit.
* National institute health stroke scale (NIHSS) Level of Consciousness score (1a) ≥ 2.
* Pre-existing disability with mRS ≥ 2.
* CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory.
* Any evidence of clinically significant bleeding, or known coagulopathy.
* INR \>1.5.
* Patients with an elevated activated partial thromboplastin time (aPTT) greater than the upper limit of normal
* Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor (i.e., dabigatran).
* Heparin flush required for an IV line. Line flushes with saline only.
* Any history of intra-cranial hemorrhage, known arteriovenous -malformation or unsecured cerebral aneurysms.
* Significant bleeding episode \[e.g. gastrointestinal (GI) or urinary tract\] within the 3 weeks before study enrollment.
* Major surgery or serious trauma in last 2 weeks.
* Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks.
* Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months.
* Uncontrolled hypertension \[Systolic blood pressure (SBP) \> 185 mmHg or diastolic blood pressure (DBP) \>110 mmHg\] that does not respond to intravenous anti-hypertensive agents.
* Surgical intervention (any reason) anticipated within the next 48 hours.
* Known history of clinically significant hepatic dysfunction or liver disease - including a current history of alcohol abuse.
* Abnormal blood glucose \<50 mg/dL (2.7 mmol/L).
* History of primary or metastatic brain tumor.
* Current platelet count \< 100,000/mm3.
* Life expectancy \< 3 months.
* Patient who, in the judgment of the investigator, needs to be on concomitant (i.e., during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, unfractionated heparin (UFH), low molecular weight heparin (LMWH), defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, glycoprotein llb/llla (GPIIb/IIIa) inhibitor or warfarin.
* Participated in any investigational study within 30 days before the first dose of study medication.
* Known hypersensitivity to Argatroban or its agents.
* Additional exclusion criteria if patient presents between 3-4.5 hours:

  1. Age \>80
  2. Currently taking oral anticoagulants (regardless of INR)
  3. A history of stroke and diabetes.
  4. NIHSS \> 25.
C: Inclusion criteria:

* Ischemic stroke with a brain lesion visualized by neuroimaging (either brain Computed Tomography (CT) or Magnetic Resonance Image (MRI)). The visualized stroke is a non-lacunar infarct , e.g. involving the cortex or \>1.5 cm (\>2.0 cm if measured on MRI diffusion-weighted images) in largest diameter if exclusively subcortical.Visualization by CT usually requires delayed imaging \>24-48 hours after stroke onset.
* The index stroke must have occurred either up to 3 months before randomization (Modified Rankin Scale(mRS) \<=3 at randomization) or up to 6 months before randomization (mRS \<=3 at randomization) in selected patients that are \>= 60 years plus at least one additional risk factor for recurrent stroke.
* Arterial imaging or cervical plus Transcranial Doppler (TCD) ultrasonography does not show extra-cranial or intracranial atherosclerosis with \>= 50% luminal stenosis in artery supplying the area of acute ischemia.
* As evidenced by cardiac monitoring for \>= 20 hours with automated rhythm detection, there is absence of AF \> 6 minutes in duration (within a 20 hour period, either as single episode or cumulative time of multiple episodes).

Further inclusion criteria apply.

Exclusion criteria:

* Modified Rankin Scale of \>=4 at time of randomization or inability to swallow medications.
* Major risk cardioembolic source of embolism such as: a) intracardiac thrombus as evidenced by transthoracic or transesophageal echocardiography, b) paroxysmal, persistent or permanent Atrial fibrillation (AF), c) atrial flutter, d) prosthetic cardiac valve (mitral or aortic, bioprosthetic or mechanical), e) atrial myxoma, f) other cardiac tumors, g) moderate or severe mitral stenosis, h) recent (\< 4weeks) myocardial infarction, i) valvular vegetations, or j) infective endocarditis.
* Any indication that requires treatment with an anticoagulant as per Investigator's judgment.
* History of atrial fibrillation (unless it was due to reversible causes such as hyperthyroidism or binge drinking, and has been permanently resolved).
* Other specific stroke etiology (i.e. cerebral arteritis or arterial dissection, migraine with aura/vasospasm, drug abuse).
* Renal impairment with estimated creatinine clearance (as calculated by Cockcroft-Gault equation) \<30mL/min at screening, or where Investigator expects creatinine clearance is likely to drop below 30mL/min during the course of the study.

Further exclusion criteria apply.
D: Inclusion Criteria:

Patients of both sexes aged ≥ 18 years with the following 4 inclusion criteria:

* One of the 3 following ischemic events in the preceding 6 months:

  * Transient ischemic attack (TIA)
  * Non-disabling brain infarcts:

    * Inclusion within 6 months after onset
    * Duration of symptoms and signs greater than 24 hours
    * Neurological signs at the time of randomization with a Rankin Scale grade 3 or less
    * With normal computed tomography (CT) scan or CT scan showing a brain infarct (even hemorrhagic infarct)
  * Peripheral embolism
* Atherosclerotic plaque in the thoracic aorta is defined as wall thickness ≥ 4 mm where the protruding material is the largest, measured at transesophageal echocardiography with multiplane transducer or a plaque less than 4 mm but with mobile component.
* Informed consent signed
* Life expectancy \> 3 years

Exclusion Criteria:

* Other causes of embolism:

  * Cardiac: endocarditis, atrial fibrillation, intra-cardiac thrombus, valvular prosthesis, rheumatic valvulopathy, left ventricular aneurysm, or ejection fraction less than 25%
  * Atherosclerotic stenosis ipsilateral to the embolic territory: internal carotid artery stenosis greater than 70%, or severe (judgment of the investigator) intracranial stenosis, or scheduled carotid endarterectomy (in that case inclusion is possible 30 days after the procedure)
  * Uncommon causes: dissection, vasculitis, procoagulant state, or sickle cell disease
* Other exclusion criteria:

  * Intercurrent illness with life expectancy less than 36 months
  * Pregnancy and non-menopausal women
  * Unwillingness to participate
  * Poor medication compliance expected
  * Toxicomania
  * Absolute indication for anticoagulant therapy (e.g. atrial fibrillation, intracardiac thrombus, prosthetic valve)
  * Scheduled for carotid endarterectomy (randomization is possible 30 days after endarterectomy)
* CT scan with an intracranial lesion other than brain infarction (space occupying mass, intracranial hemorrhage)
* Transesophageal echocardiography (TEE) with plaque ≥ 4 mm in thickness distal to the supposed embolized artery (judgement of the investigator).
* Contraindication to clopidogrel, aspirin, and oral anticoagulants

Answer: C