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

Study Overview
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Brief Summary
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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.

Detailed Description
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OPTION is a multicenter, prospective, randomized, open label, blinded-endpoint (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.

Official Title
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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

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: rhTNK-tPA
* Drug: Antiplatelet Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The clinical diagnosis is acute ischemic stroke (the criteria followed the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2018). Age≥18 years Pre-stroke mRS score≤1 points Baseline NIHSS 4-25 (both included) at the time of randomization Onset (last-seen-well) time to treatment time between 4.5 and 24 hours Informed consent from the patient or surrogate 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: Treated with intravenous thrombolysis within 72 hours Have a clear contraindication for intravenous thrombolysis Intended to proceed endovascular treatment 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 Woman of childbearing potential who is known to be pregnant or who has a positive pregnancy test on admission Brain tumor (with mass effect) Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency Coagulation Disorders caused by diseases or anticoagulants: warfarin was used with International Normalized Ratio (INR)>1.7 or PT>15s; heparin was administered within 24 hours; novel oral anticoagulants were used within 48 hours Glycoprotein IIb-IIIa inhibitors were used within the past 72 hours Baseline platelet count <100×109/L Known severe renal insufficiency with eGFR<30ml/min or serum creatinine>2.5mg/dl Undergoing hemodialysis or peritoneal dialysis; known severe intolerance to contrast media Suspected aortic dissection Parenchymal organ surgery or biopsy within the previous 1 month Any active bleeding within the previous 1 month (including gastrointestinal or urinary bleeding) Known severe allergy (more than a rash) to contrast media uncontrolled by medications Refractory hypertension (defined as persistent systolic blood pressure>185mmHg or diastolic blood pressure>110mmHg) Expected survival time<0.5 year (such as complicated with malignant tumor, serious heart and lung diseases, etc.) Participants in other interventional randomized trials that may confound the outcome assessment Other circumstances that the investigator considers inappropriate for participation in the trial or that may pose significant risks to patients (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 Presence of proximal arterial occlusion on CTA/MRA (e.g., intracranial ICA, MCA-M1 and dominant M2 segments, and vertebrobasilar arteries) Ischemic core volume>1/3 of the MCA territory defined on CT/MRI

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective, randomized, open label, blinded-endpoint (PROBE)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous rhTNK-tPA<br>rhTNK-tPA(0.25mg/kg) given as a single, intravenous bolus immediately upon randomization. Experimental treatment will be administered as a single intravenous bolus over 5-10 seconds as per the standard manufacturers' instructions for use. | Drug: rhTNK-tPA<br>* Recombinant human TNK tissue-type plasminogen activator. Patients will receive intravenous rhTNK-tPA (0.25mg/kg, maximum 25mg, administered as a bolus over 5-10 seconds).<br>|
| Active Comparator: Antiplatelet agents<br>Patients will be treated with standard guideline-directed antiplatelet treatment-choice at the discretion of the clinician. Aspirin will be the choice of most physicians; some will choose to use the clopidogrel. Standard of care medication(s) should be given immediately upon randomization. | Drug: Antiplatelet Agents<br>* Patients will receive single antiplatelet therapy-choice at the discretion of the clinician. Aspirin will be the choice of most physicians, some will choose clopidogrel.<br>* Other names: Clopidogrel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Excellent functional outcome | Proportion of subjects with mRS 0-1 at 90±7 days | 90±7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| modified Rankin Scale (mRS) score | Ordinal distribution of mRS at 90±7 days; modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 1 no clinically significant disability, 2 slight disability, 3 moderate disability but remaining able to walk unassisted, 4 moderately severe disability, 5 severe disability, and 6 death) | 90±7 days | 
| Good functional outcome | Proportion of subjects with mRS 0-2 at 90±7 days | 90±7 days | 
| Rate of successful reperfusion | >90% reduction of the Tmax>6s lesion volumes between the baseline and early follow-up at 24 hours (-2/+12 hours) | 24 hours (-2/+12 hours) | 
| Change of infarct volume from baseline to 24 hours (-2/+12 hours) | The infarct volume is determined on evaluated on CT at 24 hours (-2/+12 hours) | 24 hours (-2/+12 hours) | 
| Early clinical recovery | Proportion of subjects with NIHSS score≥8 improved compared with baseline or with NIHSS 0-1 at 24 hours (-2/+12 hours) | 24 hours (-2/+12 hours) | 
| Change of National Institutes of Health Stroke Scale (NIHSS) | Change of NIHSS score from baseline to 7 days (±2days) | 7±2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute ischemic stroke, extended time window, non-large vessel occlusion, intravenous thrombolysis