Intravenous Thrombolysis With rhTNK-tPA for Acute Non-large Vessel Occlusion in Extended Time Window

Intravenous Thrombolysis With Recombinant Human TNK Tissue-type Plasminogen Activator (rhTNK-tPA) for Acute Non-large Vessel Occlusion in Extended Time Window--A Multicenter, Prospective, Randomized, Open-label, Blinded End-point Trial

This study is designed to evaluate the efficacy of IV rhTNK-tPA between 4.5 to 24 hours from symptom onset in patients presenting with a non-large vessel occlusion ischemic stroke.

OPTION is a multicenter, prospective, randomized, open-label, blinded end-point (PROBE) controlled trial of thrombolysis with rhTNK-tPA versus standard of care. A total of 568 patients will be enrolled at approximately 40 centers around China.

Inclusion Criteria:

• Clinical diagnosis of acute ischemic stroke

• Age≥18 years

• Pre-stroke mRS score≤1 points

• Disabling stroke defined as follows:

  • Baseline NIHSS score 6-25 at the time of randomization,
  • Or NIHSS 4-5 with disabling deficit (e.g. hemianopia, aphasia, loss of hand function) as determined by the managing clinician

• Onset (last-seen-well) time to treatment time between 4.5 and 24 hours

• Written informed consent from patients or legally responsible representatives

• The presence of a Target Mismatch on CT perfusion: ischemic core volume<50ml (defined as rCBF<30%), mismatch ratio≥1.2 (Tmax>6 sec lesion/core volume lesion), mismatch volume≥10ml

Exclusion Criteria:

• Treatment with a thrombolytic within the last 72 hours or intention to receive intravenous thrombolysis
• Contraindication to thrombolysis
• Planned or anticipated treatment with endovascular therapy
• Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in a NIHSS score<4 at randomization
• Pregnancy or lactating; formal testing needed in women of childbearing potential
• Brain tumor (with mass effect)
• Hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency
• Impairment in coagulation due to comorbid disease or anticoagulant use. If on warfarin, international normalized ratio (INR) >1.7 or prothrombin time >15s; if use of any direct oral anticoagulant within the last 48 hours; if use of heparin/heparinoid within the last 24 hours
• Use of glycoprotein Ⅱb-Ⅲa inhibitors within the last 72 hours
• Baseline platelet count <100,000/μL
• Undergoing hemodialysis or peritoneal dialysis; known severe renal insufficiency with glomerular filtration rate <30ml/min or serum creatinine >220mmol/L (2.5mg/dl)
• Suspected aortic dissection
• Major surgery or biopsy within the last 1 month
• Any active bleeding within the previous 1 month (including gastrointestinal or urinary bleeding)
• Known severe, life-threatening allergy (more severe than skin rash) to contrast agents
• Severe, uncontrolled hypertension (systolic blood pressure >185mmHg or diastolic blood pressure >110mmHg)
• Any terminal illness such that the patient would not be expected to survive more than half a year
• Current participation in any investigational study that may confound outcome assessment of the study
• Any condition that, in the judgement of the investigator, is inappropriate for participation in the trial or could impose hazards to the patient (e.g. inability to understand and/or follow the study procedures and/or follow-up due to mental disorders, cognitive or emotional disorders)

Specific Neuroimaging Exclusion Criteria:

• Evidence of acute intracranial hemorrhage
• Acute large vessel occlusion on magnetic resonance/ computed tomography angiography, including internal carotid artery (ICA), middle cerebral artery M1 segment (MCA-M1）, vertebral artery and basilar artery