Please select the eligibility criteria that correspond to the clinical trial below.
Title: THrombolysis for Acute Wake-up and Unclear-onset Strokes With Alteplase at 0.6 mg/kg Trial (THAWS)
Brief Summary: The purpose of this study is to clarify efficacy and safety of MRI-based intravenous thrombolysis with alteplase for patients with acute wake-up ischemic stroke and those having acute ischemic stroke with unknown time of symptom onset.


Options:
A: Inclusion Criteria:

Clinical Inclusion Criteria

* Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g., stroke symptoms recognized on awakening)
* Last known well (without neurological symptoms) \> 4.5 hours of treatment initiation
* Measurable disabling neurological deficit (defined as an impairment of one or more of the following: language, motor function, cognition, gaze, vision, neglect)
* Age 18-80 years
* Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening)
* Written informed consent by patient or proxy

Imaging Inclusion Criteria:

* Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed
* MRI showing a pattern of "DWI-FLAIR-mismatch", i.e. acute ischemic lesion visibly on DWI ("positive DWI") but no marked parenchymal hyperintensity visible on FLAIR ("negative FLAIR") indicative of an acute ischemic lesion ≤4.5 hours of age

Exclusion Criteria:

Clinical Exclusion Criteria

* Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra-arterial thrombolysis, mechanical recanalization techniques)
* Pre-stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability corresponding to an MRS score \> 1)
* Participation in any investigational study in the previous 30 days
* Severe stroke by clinical assessment (e.g. NIHSS \> 25)
* Hypersensitivity to Alteplase or any of the excipients
* Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed in women up to 55 years of age)
* Significant bleeding disorder at present or within past 6 months
* Known haemorrhagic diathesis
* Manifest or recent severe or dangerous bleeding
* Known history of or suspected intracranial haemorrhage
* Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from aneurysm
* History of CNS damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery)
* Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel
* Current use of anticoagulants (e.g. Phenprocoumon, Warfarin, new anticoagulants such as Dabigatran) or current use of heparin and elevated thromboplastin time (low-dose subcutaneous heparin is allowed)
* Platelet count \< 100.000/mm3 (\<100G/l)
* Blood glucose \< 50 or \> 400 mg/dl (\< 2.8 or 22.2 mmol/l)
* Severe uncontrolled hypertension, i.e. systolic blood pressure \> 185 mmHg or diastolic blood pressure \>110 mmHg or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits)
* Manifest or recent bacterial endocarditis, pericarditis
* Manifest or recent acute pancreatitis
* Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations
* Neoplasm with increased bleeding risk
* Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis
* Major surgery or significant trauma in past 3 months
* Stroke within 30 days
* Life expectancy 6 months or less by judgement of the investigator
* Any condition associated with a significantly increased risk of severe bleeding not mentioned above
* Any contraindication to MRI (e.g. cardiac pacemaker)

Imaging Exclusion Criteria:

* Poor MRI quality precluding interpretation according to the study protocol
* Any sign of intracranial haemorrhage on baseline MRI
* FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion indicative of an acute ischemic lesion with a high likelihood of being \> 4.5 hours old
* Large DWI lesion volume \> 1/3 of the MCA or \> 50% of the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory (visual inspection) or \> 100 ml
* Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV-tPA treatment in the judgement of the investigator
B: Inclusion Criteria:

1. 18 to 85 years of age
2. Presenting with symptoms consistent with an acute ischemic stroke
3. Imaging evidence of an anterior circulation occlusion of the Internal Carotid Artery (ICA) terminus and/or Middle Cerebral Artery Main Stem (MCA M1) segment
4. NIHSS score \>6 at the time of randomization
5. Ability to randomize within 24 hours of stroke onset
6. Pre-stroke mRS score 0-1
7. Ability to obtain signed informed consent

Imaging evidence of moderate-large infarct defined as:

1. NCCT ASPECTS 2-5

Exclusion Criteria:

1. Females who are pregnant, or those of child-bearing potential with positive urine or serum beta Human Chorionic Gonadotropin (HCG) test
2. Known severe allergy (more than a rash) to contrast media uncontrolled by medications
3. Refractory hypertension (defined as persistent systolic blood pressure \>185 mmHg or diastolic blood pressure \>110 mmHg)
4. CT evidence of the following conditions:

   * Midline shift or herniation
   * Evidence of intracranial hemorrhage
   * Mass effect with effacement of the ventricles
5. Computed Tomography Angiography (CTA) evidence suggestive of difficult endovascular access per the treating interventionalist
6. Presence of cervical ICA occlusion (e.g., related to atherosclerotic disease or dissection)
7. Rapidly improving neurological status prior to randomization to NIHSS \<6
8. Bilateral strokes or multiple intracranial occlusions
9. Intracranial tumors
10. Known hemorrhagic diathesis, coagulation factor deficiency, or on anticoagulant therapy with an International Normalized Ratio (INR) of \>3.0 or Partial Thromboplastin Time (PTT) \>3 times of normal
11. Baseline platelet count \<30,000 per microliter (µl)
12. Life expectancy less than 90 days prior to stroke onset
13. Participation in another randomized clinical trial that could confound the evaluation of the study
14. Any other condition (in the opinion of the site investigator) that precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was performed
C: General Inclusion Criteria:

1. Clinical signs and symptoms consistent with the diagnosis of an acute ischemic stroke, and subject belongs to one of the following subgroups:

   1. Subject has failed IV t-PA therapy (defined as a confirmed persistent occlusion 60 min after administration)
   2. Subject is contraindicated for IV t-PA administration
2. Age ≥18
3. Baseline NIHSS ≥10 (assessed within one hour of measuring core infarct volume)
4. Subject can be randomized between with 6 to 24 hours after time last known well
5. No significant pre-stroke disability (pre-stroke mRS must be 0 or 1)
6. Anticipated life expectancy of at least 6 months
7. Subject willing/able to return for protocol required follow up visits
8. Subject or subject's Legally Authorized Representative (LAR) has signed the study Informed Consent form\*

   * If approved by local ethics committee and country regulations, the investigator is allowed to enroll a patient utilizing emergency informed consent procedures if neither the patient nor the representative or person of trust is available to sign the informed consent form. However, as soon as possible, the patient is informed and his/her consent is requested for the possible continuation of this research. (Not applicable to U.S. Sites.)

Imaging Inclusion Criteria:

1. \< 1/3 MCA territory involved, as evidenced by CT or MRI
2. Occlusion of the intracranial ICA and/or MCA-M1 as evidenced by MRA or CTA
3. Clinical Imaging Mismatch (CIM) defined as one of the following on MR-DWI or CTP-rCBF maps:

   1. 0-\<21 cc core infarct and NIHSS ≥ 10 (and age ≥ 80 years old)
   2. 0-\<31 cc core infarct and NIHSS ≥ 10 (and age \< 80 years old)
   3. 31 cc to \<51 cc core infarct and NIHSS ≥ 20 (and age \< 80 years old)

General Exclusion Criteria:

1. History of severe head injury within past 90 days with residual neurological deficit, as determined by medical history
2. Rapid improvement in neurological status to an NIHSS \<10 or evidence of vessel recanalization prior to randomization
3. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, e.g. dementia with prescribed anti-cholinesterase inhibitor (e.g. Aricept)
4. Seizures at stroke onset if it makes the diagnosis of stroke doubtful and precludes obtaining an accurate baseline NIHSS assessment
5. Baseline blood glucose of \<50mg/dL (2.78 mmol) or \>400mg/dL (22.20 mmol)
6. Baseline hemoglobin counts of \<7 mmol/L
7. Baseline platelet count \< 50,000/uL
8. Abnormal baseline electrolyte parameters as defined by sodium concentration \<130 mmol/L, potassium concentration \<3 mEq/L or \>6 mEq/L
9. Renal failure as defined by a serum creatinine \>3.0 mg/dL (264 µmol/L) NOTE: subjects on renal dialysis may be treated regardless of serum creatinine levels
10. Known hemorrhagic diathesis, coagulation factor deficiency, or on anticoagulant therapy with INR \> 3.0 or PTT \> 3 times normal. Patients on factor Xa inhibitor for 24-48 hours ago must have a normal PTT.
11. Any active or recent hemorrhage within the past 30 days
12. History of severe allergy (more than rash) to contrast medium
13. Severe, sustained hypertension (Systolic Blood Pressure \>185 mmHg or Diastolic Blood Pressure \>110 mmHg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using medication the subject can be enrolled
14. Female who is pregnant or lactating at time of admission
15. Current participation in another investigational drug or device study
16. Presumed septic embolus, or suspicion of bacterial endocarditis
17. Treatment with any cleared thrombectomy devices or other intra-arterial (neurovascular) therapies prior to randomization

Imaging Exclusion Criteria:

1. Evidence of intracranial hemorrhage on CT/MRI
2. CTA or MRA evidence of flow limiting carotid dissection, high-grade stenosis, or complete cervical carotid occlusion requiring stenting at the time of the index procedure (i.e., mechanical thrombectomy).
3. Excessive tortuosity of cervical vessels on CTA/MRA that would likely preclude device delivery/deployment
4. Suspected cerebral vasculitis based on medical history and CTA/MRA
5. Suspected aortic dissection based on medical history and CTA/MRA
6. Intracranial stent implanted in the same vascular territory that would preclude the safe deployment/removal of the Trevo device
7. Occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior circulation/vertebrobasilar system) as confirmed on CTA/MRA, or clinical evidence of bilateral strokes or strokes in multiple territories
8. Significant mass effect with midline shift as confirmed on CT/MRI
9. Evidence of intracranial tumor (except small meningioma) as confirmed on CT/MRI
D: Inclusion Criteria:

* Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g. acute wake-up ischemic stroke, acute ischemic stroke with unknown time of symptom onset)
* Last known well without neurological symptoms \>4.5 hours of treatment initiation
* Treatment can be started within 4.5 hours of symptom recognition (e.g. awaking)
* Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed
* Alberta Stroke Program Early CT score (ASPECTS) on initial DWI is 5 or more
* No marked parenchymal hyperintensity visible on FLAIR
* Initial NIHSS ≥2
* Written informed consent by patient or next of kin

Exclusion Criteria:

* Pre-stroke Modified Rankin Scale (mRS) \>1 (patients who have inability to carry out all daily activities and require some help or supervision)
* Contraindications in the Japanese guideline for the intravenous application of recombinant tissue-type plasminogen activator (alteplase)

  * History of nontraumatic intracranial hemorrhage
  * History of stroke within the last 1 month (excluding transient ischemic attack)
  * History of significant head/spinal injury or surgery within the last 3 months
  * History of gastrointestinal or urinary tract bleeding within the last 21 days
  * History of major surgery or significant trauma other than head injury within the last 14 days
  * Hypersensitivity to alteplase
  * Suspected subarachnoid hemorrhage
  * Concurrent acute aortic dissection
  * Concurrent hemorrhage (e.g., intracranial, gastrointestinal, urinary tract, or retroperitoneal, hemoptysis)
  * Systolic blood pressure ≥185 mmHg despite antihypertensive therapy
  * Diastolic blood pressure ≥110 mmhg despite antihypertensive therapy
  * Significant hepatic disorder
  * Acute pancreatitis
  * Blood glucose \<50mg/dL or \>400 mg/dL
  * Platelet count ≤100,000/mm3
  * International normalized ratio of prothrombin time (PT-INR) \>1.7 or Prolonged activated partial thromboplastin time (aPTT: \>1.5 times the baseline value \[\>approximately 40 seconds only as a guide\]) for patients on anticoagulation therapy or those with abnormal coagulation
* Any contraindication to MRI (e.g. cardiac pacemaker)
* Extensive early ischemic change in brain stem or cerebellum (e.g., more than half of brain stem or more than one hemisphere of cerebellum)
* Planned or anticipated treatment with surgery or endovascular reperfusion strategies (e.g., intra-arterial thrombolysis, mechanical recanalization techniques)
* Pregnant, lactating, or potentially pregnant
* Life expectancy 6 months or less by judgment of the investigator
* Inappropriate for study enrollment by judgment of the investigator

Answer: D