rhPro-UK in Acute Ischaemic Stroke Within 4.5 Hours of Stroke Onset Trial 2(PROST-2)

Study Overview
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Brief Summary
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Intravenous thrombolysis is the first-line therapy in patients with acute ischemic stroke within 4·5 hours of symptom onset, and recombinant tissue plasminogen activator (alteplase) is the preferred thrombolytic agent for this purpose. RhPro-UK is a specific plasminogen activator. rhPro-UK only acts on occlusive thrombus and has little effect on hemostatic thrombus. In addition, rhPro-UK does not form covalent complexes with protease inhibitors in plasma, so the concentrations of rhpro-UK and protease inhibitors in the blood do not decrease compared with alteplase. Therefore, rhPro-UK therapies have a potential advantage of less systemic bleeding in treated subjects. Data from several previous studies suggest that rhPro-UK is efficacious when used to treat patients with acute myocardial infarction. On April 2, 2011, rhPro-UK injection was approved by the National Medical Products Administration to treat acute myocardial infarction. Since then, rhPro-UK has been widely used to treat myocardial infarction in China. Since 2016, a phase 2 clinical trial was carried to explore the dosing of rhPro-UK in patients with acute ischemic stroke, followed by another study with a sample size of 680 patients to initially validate the efficacy and safety of the proposed dose of 35mg. The results of these studies suggested that rhPro-UK was effective, and there were no safety concerns. To further prove the efficacy and safety of rhPro-UK in patients with acute ischemic stroke, investigators conducted this phase 3 study (PROST-2).

Official Title
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A Phase III Trial to Assess the Efficacy and Safety of Recombinant Human Prourokinase in the Treatment of Acute Acute Ischaemic Stroke in 4.5 Hours After Stroke Onset

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: rhPro-UK
* Drug: rt-PA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinically diagnosed as acute ischemic stroke (according to the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2018). 18 years or older, male or female. NIH Stroke Scale（NIHSS）scores of 4 to 25. Treatment within 4.5 hours after stroke onset. The symptoms of stroke last at least 30 minutes without significant improvement before treatment. Informed consent by patient or by patient's guardians. Exclusion Criteria: Prestroke modified rankin scale of ≥2. Large areas of hypodense ischaemic changes on baseline CT（Infarction area> 1/3 of the middle cerebral artery feeding area）. Intracranial hemorrhage. Previous history of intracranial hemorrhage. Severe cerebral trauma or stroke history within 3 months. Intracranial tumor or giant intracranial aneurysm. Intracranial or intraspinal surgery within the past 3 months. Gastrointestinal or urinary bleeding within the past 3 weeks. History of major surgical procedures or severe trauma within the last 2 weeks (investigator evaluation). Puncture in 1 week which can not be oppressed. Active visceral hemorrhage. Aortic arch dissection. Bacterial endocarditis or pericarditis. Planned for thrombectomy. Patients with systolic blood pressure ≥ 185 mmHg or diastolic blood pressure ≥ 110 mmHg after anti-hypertension treatment. High risk of acute hemorrhage include platelet count<10^9/L. Received low molecular weight heparin or heparin within 24 hours. Using of thrombin inhibitors or factor Xa inhibitor within the past 48 hours. Using of oral anticoagulant drugs and PT >15s or INR >1.7. Patients with epilepsy or other mental disorders that could not be adhered to at the beginning of stroke. Blood glucose < 2.8 mmol/L or > 22.2 mmol/L. Allergies to rhPro-UK or rt-PA active ingredients or other components. Pregnant women or beastfeeding women. Participants in other clinical trials within the past month. The investigator believes that the patient is not suitable for the study.

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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhPro-UK<br>Recombinant Human Pro-urokinase (rhPro-UK) | Drug: rhPro-UK<br>* 35 mg, administered intravenously with a bolus of 15 mg within 3 minutes and the remainder by continuous infusion within 30 minutes<br>|
| Active Comparator: rt-PA<br>Alteplase(rt-PA) | Drug: rt-PA<br>* 0.9 mg/kg (maximum 90 mg), with 10% administered intravenously as a bolus, followed by 90% infusion within 1 hour<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with excellent functional outcome at 90 days | A score of 0 or 1 on the modified Rankin scale(which ranges from 0 [no symptoms] to 6 [death]) at 90 days indicated an excellent functional outcome. | 90±7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with independent functional outcome at 90 days | A score of 0-2 on the modified Rankin scale(which ranges from 0 [no symptoms] to 6 [death]) at 90 days indicated an independent functional outcome. | 90±7 days | 
| Functional handicap | The distribution of the modified Rankin scale(which ranges from 0 [no symptoms] to 6 [death]) at 90 days | 90±7 days | 
| The proportion of patients with neurological improvement at 24 hours | A reduction in NIHSS score of ≥4 or a score of 0-1 indicated neurological improvement. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts. | 22-36 hours | 
| The proportion of patients with neurological improvement at 7 days | A reduction in NIHSS score of ≥4 or a score of 0-1 indicated neurological improvement. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts. | 7 ±2 days | 
| The change of neurological function at 24 hours | NIHSS score was used to assess neurological function. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts. | 22-36 hours | 
| The change of neurological function at 7 days | NIHSS score was used to assess neurological function. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts. | 7 ±2 days | 
| Self-care ability in daily life | The Barthel Index(which ranges from 0[complete dependence on help with activities of daily living] to 100[independence]) of 95-100 at 90 days | 90±7 days | 
| All-cause death within 7 days |  | 7 days | 
| All-cause death within 90 days |  | 90 days | 
| Symptomatic intracranial hemorrhage defined as SITS-MOST |  | 22-36 hours | 
| Symptomatic intracranial hemorrhage defined as ECASSIII |  | 7 days | 
| Any intracranial hemorrhage |  | 7 days | 
| Any systematic bleeding event（defined as ISTH） |  | 7 days |