Please select the eligibility criteria that correspond to the clinical trial below.
Title: ARTSS-2: A Pilot, Phase 2b, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke
Brief Summary: Randomized controlled clinical trial to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.


Options:
A: Inclusion Criteria:

* Adult subjects (male or female ≥18 years old)
* Acute nondisabling ischemic stroke (NIHSS ≤3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the "last see normal" principle
* TIA (neurologic deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with investigational medication within 24 hours of symptoms onset. Symptom onset is defined by the "last see normal" principle
* Informed consent signed

Exclusion Criteria:

* Diagnosis of hemorrhage or other pathology, such as vascular malformation, tumor, abscess or other major nonischemic brain disease, on baseline head CT or MRI scan
* mRS score \>2 at randomization (premorbid historical assessment)
* NIHSS ≥4 at randomization
* Clear indication for anticoagulation (atrial fibrillation, mechanical cardiac valves, deep venous thrombosis, pulmonary embolism or known hypercoagulable state)
* Contraindication to investigational medications
* Thrombolysis for ischemic stroke within preceding 7 days
* History of intracranial hemorrhage
* Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anticoagulation
* Gastrointestinal bleed or major surgery within 3 months
* Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months
* TIA or minor stroke induced by angiography or surgery
* Severe noncardiovascular comorbidity with life expectancy \<3 months
* Women of childbearing age not practicing reliable contraception who do not have a documented negative pregnancy test result
* Severe renal failure, defined as Glomerular Filtration Rate (GFR) \<30 ml/min Severe hepatic insufficiency (Child-Pugh score B to C)
B: Inclusion criteria:

* Written informed consent in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and local legislation and/or regulations
* Confirmed diagnosis of Cerebral Venous or dural sinus thrombosis (CVT), with or without intracranial haemorrhage
* Completion of anticoagulation therapy for 5-15 days which has been administered until randomisation; anticoagulation must include full-dose low molecular weight heparin or unfractionated heparin
* Eligibility for treatment with an oral anticoagulant
* Further inclusion criteria apply

Exclusion criteria:

* Cerebral Venous or dural sinus thrombosis (CVT) associated with central nervous system infection or due to head trauma
* Planned surgical treatment for CVT
* Conditions associated with increased risk of bleeding
* History of symptomatic non-traumatic intracranial haemorrhage with risk of recurrence according to Investigator judgment
* Treatment with an antithrombotic regimen for an indication other than CVT and requiring continuation of that treatment for the original diagnosis without change in the regimen
* Severe renal impairment
* Active liver disease
* Pregnancy, nursing or planning to become pregnant while in the trial
* Further exclusion criteria apply
C: Inclusion criteria:

* Acute ischemic stroke, any territory, with an appropriate neuroradiologic study (head CT scan or brain MRI scan) providing results consistent with non hemorrhagic stroke
* Onset of symptoms of qualifying stroke within 48 hours prior to randomization. In patients receiving thrombolytic therapy for the acute stroke, such as tissue-type plasminogen activator (tPA), administration of study drug may not start until at least 24 hours after completion of thrombolytic therapy
* Significant motor impairment of the leg, as indicated by a NIHSS score ≥2 on item 6
* Inability to walk without assistance

Exclusion criteria:

* Females who are pregnant, breast-feeding, or of childbearing potential and not using medically acceptable and effective contraception
* Clinical evidence of VTE at screening
* Any evidence of active bleeding on the basis of clinical judgment
* Prior history of intracranial hemorrhage (including that at screening)
* Spinal or epidural analgesia or lumbar puncture within the preceding 24 hours
* Thrombolytic therapy (e.g., tPA) or intra-arterial thrombolytic therapy within the preceding 24 hours.Thrombolytic therapy is permitted for treatment of the acute stroke but must have been completed 24 hours prior to randomization.
* Comatose at screening (NIHSS score ≥2 on item 1a)
* Known or suspected cerebral aneurysm or arteriovenous malformation
* Confirmed malignancy that may pose an increased risk for bleeding or otherwise compromise follow-up or outcome assessment (e.g., lung cancer)
* Impaired hemostasis, i.e., known or suspected coagulopathy (acquired or inherited); baseline platelet count \<100,000/mm3; aPTT 1.5 X the laboratory upper limit of normal; or international normalized ratio(INR) \>1.5
* Major surgery or recent major trauma within the previous 3 months
* Anticipated need for full-dose treatment with therapeutic levels of an anticoagulant (LMWH, UFH, oral anticoagulant), e.g., for cardiogenic source of embolism or dissection
* Treatment with a LMWH or UFH at prophylactic dose for more than 48 hours prior to randomization(patients receiving LMWH or UFH less than 48 hours prior to randomization may be randomized)
* Allergy to heparin or enoxaparin sodium, or known hypersensitivity to heparin, enoxaparin, or pork products
* History of heparin or enoxaparin induced thrombocytopenia and/or thrombosis (heparin-induced thrombocytopenia \[HIT\], heparin-associated thrombocytopenia \[HAT\], or heparin-induced thrombotic thrombocytopenia syndrome \[HITTS\])
* History of hypersensitivity to iodinated contrast media and/or iodine
* Bacterial endocarditis
* Prosthetic heart valve
* Known or suspected severe anemia (Hg \<10.0 g/dL)
* Uncontrolled arterial hypertension (systolic blood pressure \[BP\] \>180 mmHg or diastolic BP \>100 mmHg) at the time of randomization or clinical hypertensive urgency
* Any other clinically relevant serious diseases, including severe liver disease or renal failure \[creatinine clearance \<30 mL/min on at least two occasions\].
* Treatment with other investigational agents or devices within the previous 30 days, planned use of other investigational drugs or devices, or previous enrollment in this study.
D: 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.

Answer: D