Clinical trial NCT03871517: INdobufen Versus aSpirin in acUte Ischemic stRokE,INSURE
Official title: INdobufen Versus aSpirin in acUte Ischemic stRokE,INSURE
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ischemic Stroke
Indobufen
Aspirin
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
First posted: 2019-03-12
Enrollment: 5438
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Any new stroke event (ischemic stroke or hemorrhagic stroke)
timeFrame: 3 months after randomization
measure: Severe or moderate bleeding
timeFrame: 3 months after randomization
Secondary outcomes:
measure: Any new stroke event
timeFrame: 1 year after randomization
measure: New vascular events
timeFrame: 1 year after randomization
measure: New ischemic stroke events
timeFrame: within 3 months and 1 year after randomization
measure: modified Rankin Scale (mRS) score was compared between 0-2 and 3-6 in the two groups.
timeFrame: During the 3-month and 1-year follow-up
measure: The proportion of mRS scores between 3 to 6 points
timeFrame: 3 months and 1 year
measure: Changes in neurological impairment
timeFrame: 3 months after randomization
measure: Quality of life at 3 months and 1 year follow-up
timeFrame: 3 months and 1 year after randomization
measure: The proportion of early lower extremity venous thrombosis.
timeFrame: 3 months after randomization
measure: All bleeding events
timeFrame: 3 months after randomization
measure: death
timeFrame: 3 months after randomization
measure: Adverse events or serious adverse events
timeFrame: 3 months after randomization
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Tian Tan Hospital, Capital Medical University
state: Beijing
Study officials:
References:
citation: Pan Y, Meng X, Chen W, Jing J, Lin J, Jiang Y, Johnston SC, Bath PM, Dong Q, Xu AD, Li H, Wang Y. Indobufen versus aspirin in acute ischaemic stroke (INSURE): rationale and design of a multicentre randomised trial. Stroke Vasc Neurol. 2022 Oct;7(5):457-461. doi: 10.1136/svn-2021-001480. Epub 2022 Apr 7.