Reperfusion Therapy in Acute Ischemic Stroke With Unclear Onset

• Study design: A prospective multicenter trial
• Study centers: 6 participating medical centers in South Korea
• Participants: Consecutive patients with acute ischemic stroke visiting the emergency room within 6 hours of the detection of stroke symptoms
• Methods

• 3 thrombolysis protocols applicable to UnCLOS patients

• IV tissue plasminogen activator (tPA) : Conventional intravenous tPA (0.9 mg/kg, 10% of the dose as a bolus and the remainder over 60 minutes) will be administered to patients within 3 hours of first found abnormal time who had no arterial occlusion or catheter-inaccessible occlusion.
• IV tPA + IA urokinase protocol : Combined intravenous tPA (0.6 mg/kg, 10% of the dose as a bolus and the remainder over 30 minutes) with intra-arterial urokinase will be administered to those within 3 hours from first found abnormal time who had catheter-accessible arterial occlusion.
• IA UK protocol : Intra-arterial urokinase will be given to those between 3 and 6 hours after first found abnormal time who had catheter-accessible arterial occlusion.
• Outcome variables

• Safety outcomes Symptomatic intracranial hemorrhage (ICH) within 48 hours from thrombolytic therapy.
• Efficacy outcomes

• Long-term clinical outcomes (modified Rankin Scale) at 3 months
• Secondary efficacy outcomes : Good vs. Poor outcomes according to mRS responder analysis, Early neurological improvement, Immediate and 5-day recanalization on MRA or CTA

Inclusion criteria

• The patient is male or female and age between 18 and 85 years
• The patient has unclear onset stroke
• Treatment of the patient can be initiated within 6 hours after first found abnormal time
• The patient has imaging-defined penumbra (at least 20%), measured by diffusion- and perfusion-weighted MRI

Exclusion criteria

• The patient has minor neurologic deficits (NIHSS <4, except aphasia or hemianopia).
• The patient has rapidly resolving neurological symptoms and the rate of improvement is projected to give the patient an NIHSS score <4 at the time of treatment.
• The patient has a pre-stroke mRS score of >1 (indicating previous disability).
• The symptoms of stroke are suggestive of subarachnoid hemorrhage.
• Evidence of infective endocarditis or septic embolism
• The patient has a history or clinical presentation of ICH, SAH, or AVM.
• Serious head trauma within 6 weeks
• Prior ischemic stroke in previous 6 weeks (except small infarct)
• Myocardial infarction in the previous 3 weeks
• Gastrointestinal or urinary tract bleeding in previous 21 days
• Major surgery in the previous 14 days
• History of biopsy of a parenchymal organ, trauma with internal organ injury or lumbar puncture within 14 days
• Arterial puncture at a non-compressible site in the previous 7 days
• Uncontrolled high blood pressure (systolic > 185 mmHg or diastolic > 110 mmHg on 3 separate occasions at least 10 min apart despite appropriate treatment)
• Evidence of active bleeding or acute trauma (fracture) on examination
• Current use of oral anticoagulants and a prolonged prothrombin time (INR >1.7)
• The patient has been treated with heparin in the previous 48 hours with prolonged aPTT, except for low dose subcutaneous LMWH with doses recommended for DVT prophylaxis
• Baseline platelet count < 100,000 mm3
• Baseline hematocrit < 25%
• Blood glucose concentration < 50 mg/dL (2.7 mmol/L) in case of CT screening
• Seizure at onset with postictal residual neurological impairments in case of CT screening
• The patient has a terminal illness.
• The patient is, in the opinion of the investigator, unlikely to comply with the clinical study protocol or is unsuitable for any other reason.
• The patient has extensive early infarction in any affected area defined as an infarcted core involving > 1/3 of MCA territory or the entire ACA or PCA territory
• The patient has well-developed parenchymal hyperintensity on FLAIR, T2*, or EPI-T2 images, or marked hypodensity on CT, indicative of subacute infarction, or enhancement with morphologic features suggesting the lesion is more than 6 hours old
• The patient has a contraindication to the imaging techniques (this means ferromagnetic objects for MRI, contraindications to contrast agent, renal disease with iodinated contrast agent in perfusion CT and CTA, etc.)
• The patient has imaging evidence of ICH or SAH, AVM, brain tumor (Incidental meningioma and microbleeds are not exclusion criteria. Incidental unruptured aneurysm that is small (< 5mm) is not an exclusion criterion).