A Study of r-PA Treating Patients With Acute Ischemic Stroke（RAISE）

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of recombinant human tissue plasminogen kinase derivatives for injection and alteplase in the treatment of patients with acute ischemic stroke within 4.5 hours.

Detailed Description
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This study is a multicenter, randomized, blind endpoint and positive drug control study. The study plans to recruit 1412 AIS patients within 4.5 hours of onset. Qualified subjects are assigned to the test drug and control drug alteplase group according to the ratio of 1:1. After receiving thrombolytic drugs, the subjects need to carry out a series of safety and effectiveness tests. The mRS score and Barthel index score visits are carried out on the 90th day (± 7 days) after thrombolysis. After the visit, the subjects can leave the group. In this study, independent blind endpoint evaluators were set up in each research center to evaluate the mRS and Barthel index score 30 and 90 days after thrombolysis.

Official Title
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A Phase III, Multicenter, Randomized, Blind Endpoint and Positive Drug Control Study of Recombinant Human Tissue Plasminogen Kinase Derivatives for Injection in the Treatment of Patients With Acute Ischemic Stroke

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: Injection of recombinant human tissue plasminogen kinase derivatives
* Drug: Recombinant human tissue plasminogen activator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 80 years（including the critical value); Acute ischemic stroke is diagnosed according to the WHO (World Health Organization) stroke diagnostic criteria, the symptoms of acute ischemic stroke are expected to be less than 4.5 hours after the time of acute ischemic stroke which is defined as the last time the patient functions well; NIHSS score at the time of treatment: from 4 points to 25 points (including 4 points and 25 points); From the signing of informed consent form to 3 months after treatment, fertile men and women of childbearing age should be absent of a birth plan and willing to take effective contraceptive measures; Participants who can understand and follow the research process, voluntarily participate, and sign an informed consent form (informed consent is voluntarily signed by the person or legal representative). Exclusion Criteria: Known to be allergic to research drugs or similar ingredients, or materials used in imaging studies; Weight >120kg or <45kg; The timing of stroke symptoms is not known; mRS score before stroke≥ 2 points; NIHSS score 1a (level of consciousness) ≥ 2 points during screening; Patients with intracerebral hemorrhage history; CT/MRI imaging examination shows signs of intracranial hemorrhage or suspected subarachnoid hemorrhage despite CT/MRI imaging findings do not show abnormalities; Severe cerebral trauma or stroke history or other severe traumas within 3 months; Assessment of Intracranial tumor, arteriovenous malformation and aneurysm before admission; Intracranial surgery, intraspinal surgery or other major surgeries within 3 months (based on the assessment of the investigators); Patients with gastrointestinal or urinary system hemorrhage in recent 3 weeks; Active visceral hemorrhage; Assessment or with history of aortic arch dissection before admission; Arterial puncture in 1 week which can not be oppressed; Subjects who have an acute bleeding tendency, including but not limited to：1) a platelet count of less than 100 × 109 / L；2) application of low molecular heparin within 24 hours before onset ; 3) Using of thrombin inhibitors or factor Xa inhibitor within 48 hours before onset ; 4) application of oral anticoagulant drugs and with an INR > 1.7 or PT>15s; Hypertension remains uncontrolled after active antihypertensive therapy, uncontrolled hypertension refers to a systolic blood pressure >185 mmHg and/or a diastolic blood pressure >110 mmHg; Blood glucose <50 mg/dl (equivalent to 2.78mmol/L) or >400 mg/dl (equivalent to 22.2mmol/L); Imaging (CT or MRI)shows large area cerebral infarction; Severe liver damage, including liver failure, cirrhosis, portal hypertension (esophageal varices), and active hepatitis; Bacterial endocarditis or pericarditis, acute pancreatitis at admission; With history of gastrointestinal ulcers, esophageal varices, aneurysms, or arterial / venous malformations within 3 months before admission; Patients who are unable to cooperate or are unwilling to cooperate with epileptic seizures, or other mental illnesses during stroke episodes; Patients who are ready to go or have undergone endovascular treatment; The restricted drug specified in the protocol or any drug that may interfere with the test results must be ingested or desired to continue to be ingested; An expected survival time of no more than 1 year due to other diseases; Patients who are participating in other trials or have participated in other trials within 30 days before randomization; Pregnancy or lactation, or women who have a positive pregnancy test result; The subject who is unsuitable for this study in the opinion of the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: experimental group<br>Recombinant human tissue plasminogen kinase derivatives(r-PA) for injection: the first intravenous bolus injection of 18mg, after 30mins, the second intravenous bolus injection of 18 mg, Push slowly for more than 2mins each time. Subjects were closely monitored during the treatment period and within 24 hours after administration. | Drug: Injection of recombinant human tissue plasminogen kinase derivatives<br>* 18mg/10ml/stick, provided by Angde Biotech<br>* Other names: r-PA;|
| Active Comparator: comparative group<br>Recombinant human tissue plasminogen activator (rt-PA) for injection: 0.9 mg/kg (maximum dose of 90 mg) intravenous, 10% of which was injected intravenously within the first 1min, and the rest continued intravenous infusion for 1 h. Subjects should be closely monitored during the treatment period and within 24 hours after administration. | Drug: Recombinant human tissue plasminogen activator<br>* 20mg/stick, 50mg/stick, provided by Shanghai Boehringer Ingelheim Pharmaceutical Co. Ltd.<br>* Other names: rt-PA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional handicap | Proportion of patients achieving a Modified Rankin Scale score of 0 to 1 on the 90th day after treatment. The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0-5. A separate category of 6 is usually added for patients who expire. The higher the score, the more severe the stroke. | on the 90th day after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Neurological Improvement | The proportion of subjects with NIHSS score ≤1 or the decrease of 4 points or more from the baseline at 24 hours and the 7th day after treatment. The National Institutes of Health Stroke Scale (NIHSS) is a 11-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on level of consciousness, eye movements, integrity of visual fields, facial movements,arm and leg muscle strength, sensation, coordination, language,speech and neglect. Each impairment is scored on an ordinal scale ranging from 0 to 2, 0 to 3, or 0 to 4. Item scores are summed to a total score ranging from 0 to 42 (the higher the score, the more severe the stroke). | at 24hours and the 7th day after treatment | 
| Scores of Neurological Improvement | NIHSS score changes from baseline at 24 hours and the 7th day after treatment. | at 24 hours and the 7th day after treatment | 
| Proportion of Long-term Improvement | Proportion of patients achieving a mRS of 0 to 2 on the 90th day after treatment. | on the 90th day after treatment | 
| Continuous changes of mRS scores | Continuous changes of mRS scores on the 30th and 90th days after treatment. | on the 30th and 90th days after treatment | 
| Barthel Index score | Proportion of patients achieving a Barthel Index score ≥95 on the 90th day after treatment. The Barthel Index of Activities of Daily Living (ADLs) measures functional disability by quantifying patient performance in 10 activities of daily life. These activities can be grouped according to self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and mobility (ambulation, transfers, and stair climbing). 5-point increments are used in scoring, with a maximal score of 100 indicating that a patient is fully independent in physical functioning, and a lowest score of 0 representing a totally dependent bed-ridden state. | on the 90th day after treatment |