INdobufen Versus aSpirin in acUte Ischemic stRokE,INSURE

Study Overview
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Brief Summary
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China has the largest burden of cerebrovascular disease in the world. About 60% to 80% of which are ischemic stroke. In recent years, stroke has replaced heart disease and tumor diseases as the first cause of death and disability in adult population. The primary purpose of this study is to evaluate the efficacy of indobufen treatment in reducing the risk of a 3-month new stroke (any type of stroke, including ischemic stroke and hemorrhagic stroke) for patients with moderate/severe ischemic stroke is not inferior to aspirin therapy.

Detailed Description
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China has the largest burden of cerebrovascular disease in the world. About 60% to 80% of which are ischemic stroke. In recent years, stroke has replaced heart disease and tumor diseases as the first cause of death and disability in adult population. The primary purpose of this study is to evaluate the efficacy of indobufen treatment in reducing the risk of a 3-month new stroke (any type of stroke, including ischemic stroke and hemorrhagic stroke) for patients with moderate/severe ischemic stroke is not inferior to aspirin therapy. The study is a multicenter, randomized, double-blind, positive drug parallel control and non-inferiority clinical design. Non-inferiority analysis was performed on the primary efficacy analysis, and both intent analysis (ITT) and compliance program set (PPS) were used for analysis. If the indobufen group was confirmed to be non-inferior to aspirin (control group), a superiority analysis was further performed to analyze whether the indobufen was superior to aspirin. At the same time, Kaplan-Meier curves were used to simulate the cumulative risk of stroke (ischemic or hemorrhagic) at 90-day follow-up, and the Cox proportional hazards model was used to calculate the hazard ratio (HR) and 95% confidence interval, Log-rank test was used to evaluate the treatment effect. All statistics will be two-sided with p<0.05 considered significant. All patients who received study drugs and with at least one safety follow-up record will be included in the safety population. The data for safety evaluation included adverse reactions observed during the trial and changes in laboratory data before and after treatment.

Official Title
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INdobufen Versus aSpirin in acUte Ischemic stRokE,INSURE

Conditions
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Ischemic Stroke, Indobufen, Aspirin

Intervention / Treatment
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* Drug: Indobufen
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male aged≥18 years and<80years. Acute moderate/severe ischemic stroke, 4≤NIHSS（National Institute of Health stroke scale）≤18 at the time of randomization. Patients can be randomized within 72 hours of symptoms onset. Provision of informed consent prior to any study specific procedures. * Symptom onset is defined by the last seen normal principle Exclusion Criteria: Diagnosis of intracerebral hemorrhage such as cerebral hemorrhage, subarachnoid hemorrhage, etc. Diagnosis of hemorrhage or other pathology, such as vascular malformation, tumor, abscess or other major non-ischemic brain disease (e.g., multiple sclerosis) on baseline head CT or MRI. Moderate to severe ischemic stroke induced by angioplasty/vascular surgery. Modified Rankin Scale Score>2 at randomization (pre-morbid historical assessment). History of aneurysm (including intracranial aneurysm or peripheral aneurysms). Clear indication for anticoagulation (presumed cardiac source of embolus, e.g., atrial fibrillation, atrial myxoma, prosthetic cardiac valves known or suspected endocarditis). History of Hemostatic disorder, systemic bleeding, thrombocytopenia or neutropenia. History of previous symptomatic non-traumatic intracerebral bleed or cerebral artery amyloidosis. Gastrointestinal (GI) bleed within the past 6 months before randomization. Major surgery within the past 3 months before randomization. Severe renal or hepatic insufficiency. (Severe hepatic insufficiency is defined as alanine aminotransferase (ALT) value>3 times normal upper limit or Aspartate aminotransferase (AST)>2 times normal upper limit; Severe renal insufficiency is defined as creatinine>2 times normal upper limit). Diagnosis or of acute coronary syndrome. Other antithrombotic therapy are required during the study, including antiplatelet therapy(such as open-labeled aspirin, GPIIb/IIIa inhibitors, clopidogrel, ticagrelor, prasugrel, dipyridamole, ozagrel, cilostazol, etc.) and anticoagulant therapy(such as warfarin, thrombin and factor Xa inhibitors, bivalirudin, hirudin, argatroban, heparin and low molecular heparin, etc.). Within randomized 24 hours prior to any venous or arterial thrombolysis, mechanical bolt, snake venom, defibrase, lumbrokinase, etc. Heparin or oral anticoagulants were used within 10 days of randomization. Have a history of drug or food allergy and are known to be allergic to the study drug ingredients Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months (if clinically indicated, vascular imaging should be performed prior to randomization whenever possible) Anticipated requirement for long-term (>7 days) non-steroidal antiinflammatory drugs (NSAIDs). The blood pressure needs to be controlled within the range of 90mmHg/60mmHg to 220mmHg/120mmHg. Suffering from serious cardiopulmonary disease, the researchers believe that it is not suitable for this study Patients with life expectancy<3 months or patients who are unable to complete the study for other reasons. Women of childbearing age who are negative in pregnancy test but refuse to practice reliable contraception. Women who are pregnant or lactating. Involving in other investigational drug or device tests within the past 30 days before randomization. Inability of the patient to understand and/or comply with study procedures and/or follow-up due to mental illness, cognitive or emotional disorders

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Indobufen<br>Drug: Indobufen and aspirin mimetic Day 1 to 90±7: The first time : Indobufen 100mg + aspirin mimetic The second time: indobufen 100mg | Drug: Indobufen<br>* Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme thereby suppressing thromboxane synthesis.<br>|
| Active Comparator: Aspirin<br>Drug: Aspirin and Indobufen mimetic Day 1 to 90±7: The first time : aspirin 100mg+ Indobufen mimetic, The second time: indobufen mimetic. | Drug: Aspirin<br>* Aspirin is a salicylate (sa-LIS-il-ate). It works by reducing substances in the body that cause pain, fever, and inflammation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any new stroke event (ischemic stroke or hemorrhagic stroke) | To evaluate the efficacy of indobufen treatment in reducing the risk of a 3-month new stroke (any type of stroke, including ischemic stroke and hemorrhagic stroke) for patients with moderate/severe ischemic stroke is not inferior to aspirin therapy. | 3 months after randomization | 
| Severe or moderate bleeding | GUSTO definition | 3 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any new stroke event | ischemic stroke or hemorrhagic stroke | 1 year after randomization | 
| New vascular events | ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death | 1 year after randomization | 
| New ischemic stroke events | New ischemic stroke events | within 3 months and 1 year after randomization | 
| modified Rankin Scale (mRS) score was compared between 0-2 and 3-6 in the two groups. | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It has become the most widely used clinical outcome measure for stroke clinical trials. The scale runs from 0-6, running from perfect health without symptoms to death: 0 - No symptoms.1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.3 - Moderate disability. Requires some help, but able to walk unassisted.4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.6 - Dead. The mRS scores between 3 to 6 points are considered to be poor functional outcome. | During the 3-month and 1-year follow-up | 
| The proportion of mRS scores between 3 to 6 points | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It has become the most widely used clinical outcome measure for stroke clinical trials. The scale runs from 0-6, running from perfect health without symptoms to death: 0 - No symptoms.1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.3 - Moderate disability. Requires some help, but able to walk unassisted.4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.6 - Dead. The mRS scores between 3 to 6 points are considered to be poor functional outcome. | 3 months and 1 year | 
| Changes in neurological impairment | changes in National Institutes of Health Stroke Scale (NIHSS) score at 3 months compared to baseline. The NIHSS is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0. Stroke severity: 0 No stroke symptoms;1-4 Minor stroke;5-15 Moderate stroke;16-20 Moderate to severe stroke;21-42 Severe stroke | 3 months after randomization | 
| Quality of life at 3 months and 1 year follow-up | We will use the EQ-5D-5L scale to evaluate the quality of life. EQ-5D-5L is a standardized instrument for measuring generic health status. It has been widely used in population health surveys, clinical studies, economic evaluation and in routine outcome measurement in the delivery of operational healthcare. The EQ-5D-5L has five domain scales (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression) and five levels for each domain. | 3 months and 1 year after randomization | 
| The proportion of early lower extremity venous thrombosis. | The proportion of early lower extremity venous thrombosis. | 3 months after randomization | 
| All bleeding events | all bleeding: including severe or moderate hemorrhage, intracranial hemorrhage | 3 months after randomization | 
| death | death | 3 months after randomization | 
| Adverse events or serious adverse events | such as gastrointestinal reaction, gastrointestinal bleeding and renal impairment | 3 months after randomization |