Study on Tirofiban With Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction

Study Overview
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Brief Summary
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Perforating artery territorial infarction (PAI) refers to a single ischaemic lesion <20 mm in a single perforating arterial territory and branch atheromatous disease (BAD) is a important etiological factor. BAD related infarction accounts for 10%-15% ischemic cerebral infarction and is closely related to early neurological deterioration (END). Among patients with BAD, dual antiplatelet (clopidogrel plus aspirin) did not significantly reduce the risk of recurrent stroke. The primary purpose of this study is to assess the efficacy and safety of tirofiban combined with aspirin versus placebo combined with aspirin in reducing the risk of recurrence and progression of stroke at 90 days in patients with acute penetrating artery territory infarction.

Detailed Description
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Perforating artery territorial infarction (PAI) constitute about 25% of ischemic strokes, including three pathophysiological mechanisms - lipohyalinosis, microatheroma and large parent artery plaque. The latter two are prone to stroke recurrence and early neurological deterioration. Aspirin plus clopidogrel are effective antiplatelet therapy for PAI patients with parent artery stenosis, but controversial in patients with branch atheromatous disease (BAD). Early rapid initiation of platelet aggregation inhibitors, such as Tirofiban, a GPIIb/IIIa receptor antagonist, may benefit those patients. The primary purpose of this study is to assess the efficacy and safety of tirofiban combined with aspirin versus placebo combined with aspirin in reducing the risk of recurrence and progression of stroke at 90 days in patients with acute penetrating artery territory infarction caused by BAD. This is a prospective, randomized, multicenter, double-blind clinical trial. In 40 centers in China, 970 patients with the following situations will be enrolled: single acute infarction of penetrating artery territory within 48 hours of onset, which involves at least 2 axial layers, or whose maximum diameter ≥15mm, or connected to the ventral surface of the median pons without crossing the midline on DWI image, no severe stenosis (defined as > 70%) of parent artery. Patients will be randomly assigned into 2 groups according to the ratio of 1:1: Tirofiban (Day 1) + Aspirin (Day 1-90) Placebo (Day 1) + Aspirin (Day 1-90) Face to face interviews will be made on baseline, 24 hours after randomization, day 7 after randomization, discharge day, and day 90 after randomization. Survival curves will be estimated for the primary outcome using the Kaplan-Meier procedure and compared using a Cox regression model Wald test, stratified by the opposite arm of the factorial design. Safety outcomes will be calculated using the Kaplan-Meier curve to simulate the 3-month cumulative risk, and the Cox proportional hazards model to calculate the HR and 95% confidence interval. The primary endpoints include recurrent stroke and early progression of stroke. The secondary endpoints include composite vascular events (stroke, myocardial infarction, and cardiovascular death), disability or death (mRS 2-6), improvement of neurological function and EQ-5D score. The safety endpoints include severe hemorrhage events, symptomatic and non-symptomatic intracranial hemorrhage, moderate hemorrhage, vascular death, overall mortality and (serious) adverse event.

Official Title
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Study on Tirofiban With Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction: A Randomized, Double-blinded, Placebo-controlled, Multi-center Trial

Conditions
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Branch Atheromatous Disease

Intervention / Treatment
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* Drug: Tirofiban hydrochloride sodium chloride injection
* Drug: Tirofiban hydrochloride sodium chloride injection placebo
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-80 years old; No gender limitation; Within 48 hours of onset; Clinical symptoms and signs suggest acute single infarction of penetrating artery territory (no cortical involvement, no multifocal involvement, NIHSS ≤10 and consciousness-1a ≤1); DWI suggests single infarction (diameter < 30mm) of penetrating artery territory (basal ganglia, internal capsule, thalamus, pons, etc.), which involves at least 2 axial layers, or its maximum diameter ≥15mm, or it is connected to the ventral surface of the pons, closing to but not crossing the midline, and located in one side; No severe stenosis (defined as > 70%) of parent artery giving off the responsible penetrating artery; The patient or his / her legal representative is able and willing to sign the informed consent. Exclusion Criteria: History of intracranial hemorrhage (subarachnoid hemorrhage and cerebral hemorrhage); History of intracranial tumors, cerebral arteriovenous malformation, or aneurysm; Emergency endovascular intervention or intravenous thrombolysis before randomization; Dual antiplatelet therapy currently or within 14 days of randomization (excluding use of aspirin and clopidogrel after onset without loading dose of clopidogrel); Use of other antiplatelet drugs (ticagrelor, cilostazol, etc.), anticoagulant drugs, snake venom, defibrase, lumbrukinase or other defibrase treatments after onset; Expected long-term use of non-investigational antiplatelet drugs or non-steroidal anti-inflammatory drugs; With severe stenosis (> 70%) of parent artery giving off responsible penetrating artery; Definite indications for anticoagulation (suspicion of cardioembolism, e.g. atrial fibrillation, known heart valve prosthesis, atrial myxoma, endocarditis, etc.) or definite indications for dual antiplatelet therapy (e.g. recent coronary or cerebral artery stent implantation); Severe hepatic or renal insufficiency before randomization (severe hepatic insufficiency refers to ALT or AST > 3 times the upper limit of normal; severe renal insufficiency refers to creatinine clearance rate (CCr) < 30ml/min); Hemorrhagic tendency (including but not limited to)：PLT<100×109/L; heparin treatment within 48h; APTT ≥ 35s; current use of warfarin, INR > 1.7; current use of novel oral anticoagulants; current use of direct thrombin or factor Xa inhibitor; Resistant hypertension which could not be controlled by medicine (SBP > 180mmHg or DBP > 110mmHg); History of obvious head trauma or stroke within three months of randomization; History of intracranial or intramedullary surgery within three months of randomization; History of major surgery or severe physical trauma within one month of randomization; Severe neurological defects (mRS ≥ 2) before the onset; Acute pericarditis; Hemorrhagic retinopathy; Childbearing-age women who do not take effective methods of contraception without negative records of pregnancy tests; Known to be allergic to tirofiban; Other surgical or interventional therapy planned within 3 months requiring experimental drugs discontinuation; Life expectancy < 6 months due to any terminal illness; Patients who are undergoing experimental drugs or instruments; Other conditions which suggest participants are unsuitable for this study, e.g. inability for understanding and / or obeying research procedures and / or follow-up due to mental diseases, cognitive or mood disturbance, or with MRI contraindications, etc.

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: Tirofiban group<br>This group will receive tirofiban and aspirin. Day 1: Tirofiban injected intravenously for 24 hours and aspirin of 100-300 mg. Tirofiban will be injected at 4 ug/kg/ min for the first 30 minutes and 0.1 ug/kg/min for the next 24 hours. Day 2-90: Aspirin 100mg per day. | Drug: Tirofiban hydrochloride sodium chloride injection<br>* Day 1: Tirofiban will be given by bolus injection at 0.4ug/kg/min for the first 30 minutes, followed by a continuous infusion at 0.1ug/kg/min for the next 24 hours.<br>Drug: Aspirin<br>* Day 1: Aspirin 100-300mg per day Day 2-90: Aspirin 100mg per day<br>|
| Placebo Comparator: Tirofiban placebo group<br>This group will receive tirofiban placebo and aspirin. Day 1: Tirofiban placebo injected intravenously for 24 hours and aspirin of 100-300 mg. The placebo will be injected at the same rate with Tirofiban group. Day 2-90: Aspirin 100mg per day. | Drug: Tirofiban hydrochloride sodium chloride injection placebo<br>* Day 1: Tirofiban placebo will be injected at the same rate with experimental group.<br>Drug: Aspirin<br>* Day 1: Aspirin 100-300mg per day Day 2-90: Aspirin 100mg per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with new stroke | Symptoms and signs of acute neurological deficits caused by sudden focal or whole brain, spinal cord, or retinal vascular damage, which are related to cerebral circulatory disorders, including hemorrhagic and ischemic stroke. | 90 days after randomization | 
| Number of participants with early progression of stroke | NIHSS score increasing by ≥ 2 points, or the score of hemiplegia increasing by≥1 point, or the score of conscious disturbance increasing by ≥ 1 point compared with baseline within 7 days of onset, and intracranial hemorrhage is excepted by CT or MRI. Exacerbations not attributable to stroke are also excluded such as cardiac failure, liver and renal failure, etc. | 7 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with new stroke or stroke progression | Hemorrhagic and ischemic stroke; NIHSS score increasing by ≥ 2 points, or the score of hemiplegia increasing by≥1 point, or the score of conscious disturbance increasing by ≥ 1 point compared with baseline within 7 days of onset. | 24 hours and 7 days after randomization | 
| Number of participants with composite vascular events | Symptomatic stroke, myocardial infarction and vascular death. | 90 days after randomization | 
| Number of participants with disability or death | The modified Rankin Scale (mRS) is 2-6 points. | 90 days after randomization | 
| Number of participants with improvement of neurological function | NIHSS score increasing by ≥ 4 points or increasing to 0-1 points compared with baseline. | 24 hours, 7 days, and 90 days after randomization | 
| EuroQol five dimensions questionnaire (EQ-5D) | It includes a descriptive system(DS) and a visual analogue scale(VAS). Two indicators are index value(ranged 0-1) and visual score(ranged 0-100) with higher scores corresponding to better health status. | 90 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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branch atheromatous disease, perforating artery territorial infarction, tirofiban, aspirin, randomized controlled trial, multicenter study, double blind study, placebo-controlled