ProUrokinase in Mild IsChemic strokE (PUMICE)

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety and efficacy of rhPro-UK (35mg) versus standard medical treatment in acute mild ischemic stroke within 4.5 hours of symptom onset.

Detailed Description
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After being informed about the study and potential risks, patients who meet the eligibility requirements will be randomized to recombinant human Prourokinase for injection (rhPro-UK) or standard medical treatment in a 1:1 ratio. Written informed consent will be needed.

Official Title
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Recombinant Human Prourokinase（rhPro-UK）for Injection Versus Standard Medical Treatment for Acute Mild Ischemic Stroke (NIHSS≤5) Within 4.5 Hours After Symptom Onset

Conditions
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Ischemic Stroke, Mild, Thrombosis

Intervention / Treatment
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* Drug: Recombinant Human Prourokinase for Injection (rhPro-UK)
* Drug: standard medical treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years, any gender; Acute ischemic stroke symptom onset within 4.5 hours prior to enrollment; onset time refers to 'last normal time'; Pre-stroke mRS score≤ 1; Baseline NIHSS ≤ 5 (both included); Written informed consent from patients or their legally authorized representatives Exclusion Criteria: Rapidly improving symptoms at the discretion of the investigator; Intended to proceed to endovascular treatment during 90 days (including mechanical thrombectomy, stent insertion or balloon expansion); Allergy to rhPro-UK and it's components (human albumin, mannitol); NIHSS consciousness score 1a >2, or epileptic seizure, hemiplegia after seizures (Todd's palsy) or combined with other nervous/mental illness unable to cooperate or unwilling to cooperate; Persistent blood pressure elevation (systolic ≥180 mmHg or diastolic ≥100 mmHg), despite blood pressure lowering treatment; Blood glucose <2.8 or >22.2 mmol/L (on random glucose testing is acceptable); Active internal bleeding or at high risk of bleeding, e.g.: Major surgery, trauma or gastrointestinal or urinary tract haemorrhage within the previous 21 days, or arterial puncture at a non-compressible site within the previous 7 days; Any known impairment in coagulation due to comorbid disease or anticoagulant use. If on warfarin, then INR >1.7 or prothrombin time >15 seconds; if use of any direct thrombin inhibitors or direct factor Xa inhibitors or new oral anticoagulants (NOAC) during the last 48 hours unless reversal of effect can be achieved with a reversal agent (by idarucizumab) or sensitivity laboratory test values greater than the upper limit of normal (eg, activated partial thromboplastin time (aPTT), international normalized ratio (INR), platelet count, thrombin time (TT), or appropriate factor Xa activity assay); if on any full dose heparin/heparinoid during the last 24 hours or with an elevated aPTT greater than the upper limit of normal; Known defect of platelet function or platelet count below 100,000/mm3 (but patients on antiplatelet agents can be included); Ischemic stroke or myocardial infarction in previous 3 months, previous intracranial haemorrhage, severe traumatic brain injury or intracranial or intraspinal operation in previous 3 months, or known intracranial neoplasm (except for neuroectodermal tumors, such as meningiomas), arteriovenous malformation or giant aneurysm; Any terminal illness such that patient would not be expected to survive more than 1 year Large cerebral infarction (infarct size > 1/3 MCA territory) on CT or MRI; Acute or past intracerebral hemorrhage (ICH) identified by CT or MRI (including intraparenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural/epidural hematoma); Pregnant women, nursing mothers, or reluctant to agree taking effective contraceptive measures during the period of trial subjects; Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study; Participation in other interventional clinical trials within the previous 3 months.

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: A multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) controlled trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhPro-UK (35mg)<br>rhPro-UK: 35 mg (5 mg per vial, 7 vials in total) Dissolve 15mg (3 vials) of rhPro-UK in 10ml of saline and intravenous bolus within 3 minutes, and dissolve the remaining 20mg (4 vials) in 90ml of saline and intravenous drip within 30 minutes. (Note: after adding saline, overturn it gently once to twice, do not shake vigorously, so as to avoid foaming of the rhPro-UK solution and reduce the efficacy). | Drug: Recombinant Human Prourokinase for Injection (rhPro-UK)<br>* 15mg of rhPro-UK intravenous bolus within 3 minutes, and the remaining 20mg intravenous drip within 30 minutes.<br>* Other names: Puyouke;|
| Active Comparator: standard medical treatment<br>Standard antiplatelet or anticoagulant treatment at the discretion of local investigators according to the 'Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018'. | Drug: standard medical treatment<br>* Standard antiplatelet or anticoagulant treatment at the discretion of local investigators.<br>* Other names: Aspirin, clopidogrel, anticoagulant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The modified Rankin Scale score (mRS) ≤ 1 at 90 days | The proportion of the modified Rankin Scale score (mRS) ≤ 1 at 90 days. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ordinal distribution of mRS at 90 days | Ordinal distribution of mRS at 90 days | 90 days | 
| mRS score ≤ 2 at 90 days | The proportion of mRS score ≤ 2 at 90 days | 90 days | 
| Early neurological functional improvement | Clinical response rate at 24 hours defined as an improvement on NIHSS score ≥ 4 points compared with the initial deficit or NIHSS score ≤ 1 point | 24 hours | 
| Barthel index of 75-100 points at 90 days | The proportion of Barthel index of 75-100 points at 90 days | 90 days | 
| Quality of Life (EQ-5D-5L) at 90 days | The value of Quality of Life (EQ-5D-5L) at 90 days | 90 days | 
| Activities of Daily Living (Lawton IADL) at 90 days | The score of Activities of Daily Living (Lawton IADL) at 90 days | 90 days | 
| Symptomatic intracranial hemorrhage within 36 hours | The rate of symptomatic intracranial hemorrhage within 36 hours (as defined by ECASS III) | 36 hours | 
| All-cause death at 90 days | All-cause mortality at 90 days | 90 days | 
| Systematic bleeding at 90 days | The rate of systematic bleeding at 90 days (as defined by GUSTO: moderate and severe bleeding) | 90 days | 
| Adverse events (AEs)/ serious adverse events (SAEs) within 90 days | The proportion of AEs/SAEs within 90 days | 90 days |