Efficacy and Safety of Tirofiban for Patients With BAD (BRANT)

Study Overview
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Brief Summary
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Branch atheromatous disease (BAD)-related stroke, characterized by subcortical single infarcts without severe stenosis of the large artery, but with a clear atherosclerotic mechanism, is now regarded as a separate stroke type. BAD is associated with early neurological deterioration and poor prognosis, but is lack of effective therapy. The goal of this randomized controlled trial is to test the efficacy and safety of intravenous tirofiban in patients with acute ischemic stroke caused by branch atheromatous disease. The main question it aims to answer is: Compared with standard antiplatelet therapy based on current stroke guideline, whether tirofiban used in acute phase of BAD could improve the proportion of excellent functional outcome (modified Rankin Scale: 0-1) at 90 days. Researcher will also compare the rate of major bleeding between treatment and control groups.

Detailed Description
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BRANT study is a multicenter, randomized, open label, blinded endpoint, Parallel controlled trial with the primary null hypothesis that, in patients with acute BAD-related stroke, there is no difference in the proportion of excellent outcome in those treated with intravenous Tirofiban compared with those treated with standard antiplatelet therapy based on guideline when subjects are randomized within 48 hours of stroke onset. The primary objective is to determine whether intravenous tirofiban (a loading dose of 0.4ug/kg/min*30min followed by a maintenance dose of 0.1ug/kg/min*47.5h) is effective in increasing the proportion of excellent functional outcome (mR: 0-1) at 90 days, when initiated within 48 hours of onset. The active comparator is standard antiplatelet therapy based on guideline [ie, 1) aspirin 150-300 mg qd, OR 2) aspirin 100 mg qd plus clopidogrel 75 mg qd] for 48 hours. Patients with acute BAD-related stroke between 18 and 75 years old, who can be randomized within 48 hours of onset, and meet the BAD Diagnostic Imaging Criteria, will be enrolled. All patients will conduct MRI before randomization. Subjects will be randomized 1:1 (Tirofiban: Standard antiplatelet therapy). The subjects' eligibility will be assessed by site investigator prior to accessing the Randomization Module, which is generated via the dynamic block randomization method. Only certified and trained personnel can access the randomization website, who will get the information of treatment (ie, Tirofiban or standard antiplatelet therapy) after the subject has be determined eligible. The treatment period is 48 hours for both study groups. A total of 516 eligible patients will be enrolled. Each participant will be followed for 90 days from randomization. The primary outcome will be assessed by well-trained senior neurologists blinded to the treatment. All the clinical and safety events will be re-examined by the Clinical Event Committee (CEC), who are blinded during all procedures.

Official Title
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Efficacy and Safety of Tirofiban in Patients With Acute Branch Atheromatous Disease (BAD)- Related Stroke (BRANT)

Conditions
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Branch Atheromatous Disease

Intervention / Treatment
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* Drug: Tirofiban
* Drug: Aspirin tablet
* Drug: Clopidogrel tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18-75 years old Acute ischemic stroke Time from onset to randomization ≤48h; if onset time is unknown, time from last known well to randomization ≤48h Meet the following BAD Diagnostic Imaging Criteria 4.1. DWI infarcts: single (isolated) deep (subcortical) infarcts; 4.2. The culprit arteries are either Lenticulostriate artery (LSA) or Paramedian pontine artery (PPA), and the infarct lesion on DWI conforms to one of the following characteristics (A/B): A. LSA: 1) Comma-like infarct lesions with Fan-shaped extension from bottom to top in the coronary position; or 2) ≥ 3 layers (layer thickness 5-7 mm) on axial DWI brain images; B. PPA: The infarct lesion extends from the deep pons to the ventral pons on the axial DWI brain images; 4.3. No more than 50% stenosis on the parent artery of the criminal artery (i.e. corresponding basilar or middle cerebral artery) (Confirmed by magnetic resonance angiography [MRA] or computed tomography angiography [CTA] or digital substraction angiography [DSA]). Singed informed consent by the patient or legally authorized representatives. Exclusion Criteria: Transient ischemic attack (TIA) Intracranial hemorrhagic diseases, vascular malformations, aneurysms, brain abscesses, malignant space-occupying lesions, or other non-ischemic intracranial lesions detected by baseline CT/MRI, or MRA/CTA/DSA; Presence of ≥50% stenosis in extracranial artery in tandem relationship ipsilateral to the lesion; Cardiogenic embolism: atrial fibrillation, myocardial infarction, heart valve disease, dilated cardiomyopathy, infective endocarditis, atrioventricular block disease, heart rate less than 50 beats per minute Have received or plan to receive endovascular therapy or thrombolysis after onset; Stroke of other clear causes, e.g., moyamoya disease, arterial entrapment, vasculitis, etc. modified Rankin Scale ≥2 before onset Use of tirofiban within 1 week before or after onset Low platelets (<100×10^9 /L), or Prothrombin time >1.3 times of the upper normal limit, or INR >1.5, or other systemic hemorrhagic tendencies such as hematologic disorders Elevation of ALT or AST more than 1.5 times the upper normal limit; Glomerular filtration rate <60 ml/min/1.73m^2 Known malignant tumors History of trauma or major surgical intervention within 6 weeks prior to onset History of intracranial hemorrhage Active or recent history(within 30 days prior to onset) of clinical bleeding (e.g., gastrointestinal bleeding) Malignant hypertension (systolic blood pressure >200 mmHg, or diastolic blood pressure >120 mmHg) Life expectancy ≤ 6 months Contraindications of 3 T MRI examination Pregnant or lactating women Have participated in another clinical trial within 3 months prior to the date of informed consent, or are participating in another clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: multi-center, randomized, open label, blinded endpoint, parallel controlled trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tirofiban group<br>Intravenous tirofiban will be administered immediately after randomization for a total duration of 48h with a loading dose of 0.4ug/kg/min*30min, followed by a maintenance dose of 0.1ug/kg/min*47.5h. | Drug: Tirofiban<br>* Tirofiban, a GPIIb/IIIa receptor inhibitor. Intravenous administration.<br>* Other names: Tirofiban Hydrochloride and Sodium Chloride Injection;|
| Active Comparator: Standard antiplatelet therapy group<br>Standard antiplatelet therapy based on Chinese stroke guideline will be administered after randomization for a total duration of 48h, as the two following types: 1) aspirin 150-300 mg qd, or 2) aspirin 100 mg qd plus clopidogrel 75 mg qd. The time for administration of antiplatelet drugs will be determined by the doctor in conjunction with the participants' use of antiplatelet or anticoagulant medication in the 24h prior to randomization, but the drug should be given as soon as possible after randomization. | Drug: Aspirin tablet<br>* Aspirin. Oral administration.<br>Drug: Clopidogrel tablet<br>* Clopidogrel. Oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Excellent functional outcome | Primary efficacy outcome: Excellent functional outcome is defined as modified Rankin Scale score: 0-1. Modified Rankin Scale, a commonly used scale for measuring the degree of dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. 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 - Death. | 90 days | 
| Proportion of major bleeding | Primary safety outcome: Participants with major bleeding defined by the PLATO criteria, confirmed by the Clinical Event Committee. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Excellent functional outcome | modified Rankin Scale score: 0-1 | 7 days | 
| Early neurological deterioration | The presence of END is determined by an increase of ≥ 4 points in the NIHSS or an increase of ≥2 points in the NIHSS motor score. In addition, NIHSS motor score refers to bilateral upper and lower extremity mobility scores. The baseline NIHSS score for the calculation of END is the first clinician-evaluated and recorded NIHSS score after onset. The time frame for post-randomization END is within 7 days of randomization. | 7 days of randomization | 
| NIHSS score | 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. | 7 days and 90 days | 
| Barthel index score | The Barthel Index (BI) is tool to measure the extent to which somebody can function independently and has mobility in activities of daily living (ADL), including 10 aspects: feeding, bathing, grooming, dressing, bowel control, bladder control, toileting, chair transfer, ambulation and stair climbing. Higher score indicates better performance in activities of daily living. | 7 days and 90 days | 
| Ischemic stroke | Number of participants with new-onset ischemic stroke, confirmed by senior neurologists and the Clinical Event Committee. | 7 days and 90 days | 
| Stroke | Number of participants with new-onset ischemic or hemorrhagic stroke, confirmed by senior neurologists and the Clinical Event Committee. | 7 days and 90 days | 
| TIA | Number of participants with new-onset transient ischemic attack (TIA), confirmed by senior neurologists and the Clinical Event Committee. | 7 days and 90 days | 
| Composite endpoint | Number of participants with new-onset stroke, myocardial Infarction, or all-cause death, confirmed by the Clinical Event Committee. | 7 days and 90 days | 
| Proportion of Major bleeding | Proportion of major bleeding defined by the PLATO criteria. | 7 days | 
| Serious adverse events | Serious adverse events | 7 and 90 days | 
| Adverse events | Adverse events | 7 and 90 days | 
| All-cause death | All-cause death | 7 and 90 days | 
| Changes in hemoglobin | Blood test of the count of hemoglobin, g/L | 48 hours | 
| Changes in the count of red blood cell | Blood test of the count of red blood cell, 10^12/L | 48 hours | 
| Changes in the count of white blood cell | Blood test of the count of white blood cell, 10^9/L | 48 hours | 
| Changes in the count of platelets | Blood test of the count of platelets, 10^9/L | 48 hours | 
| Changes in alanine transaminase | Serum biochemical test for alanine transaminase | 48 hours | 
| Changes in aspartate aminotransferase | Serum biochemical test for aspartate aminotransferase | 48 hours | 
| Changes in direct bilirubin | Serum biochemical test for the concentration of direct bilirubin | 48 hours | 
| Changes in indirect bilirubin | Serum biochemical test for the concentration of indirect bilirubin | 48 hours | 
| Changes in concentration of Na | Serum biochemical test for the concentration of sodium, mmol/L | 48 hours | 
| Changes in the concentration of K | Serum biochemical test for the concentration of potassium, mmol/L | 48 hours | 
| Changes in the concentration of creatinine | Serum biochemical test for creatinine | 48 hours | 
| Changes in the concentration of albumin | Serum biochemical test for albumin | 48 hours | 
| Changes in the urinary occult blood | The test of urine blood (BLD). Negative or positive. | 48 hours | 
| Changes in the fecal occult blood | The test of occult blood (Occult blood, OB). Negative or positive | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Branch atheromatous disease, Tirofiban, Stroke, Treatment Outcome, Magnetic Resonance Imaging