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

Phase 3Active Not RecruitingNCT06037889

Peking Union Medical College Hospital516 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age: 18-75 years old 2. Acute ischemic stroke 3. Time from onset to randomization ≤48h; if onset time is unknown, time from last known well to randomization ≤48h 4. 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 \[DSA\]). 5. Singed informed consent by the patient or legally authorized representatives. Exclusion Criteria: 1. Transient ischemic attack (TIA) 2. 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; 3. Presence of ≥50% stenosis in extracranial artery in tandem relationship ipsilateral to the lesion; 4. Cardiogenic embolism: atrial fibrillation, myocardial infarction, heart valve disease, dilated cardiomyopathy, infective endocarditis, atrioventricular block disease, heart rate less than 50 beats per minute 5. Have received or plan to receive endovascular therapy or thrombolysis after onset; 6. Stroke of other clear causes, e.g., moyamoya disease, arterial entrapment, vasculitis, etc. 7. modified Rankin Scale ≥2 before onset 8. Use of tirofiban within 1 week before or after onset 9. 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 10. Elevation of ALT or AST more than 1.5 times the upper normal limit; 11. Glomerular filtration rate \<60 ml/min/1.73m\^2 12. Known malignant tumors 13. History of trauma or major surgical intervention within 6 weeks prior to onset 14. History of intracranial hemorrhage 15. Active or recent history(within 30 days prior to onset) of clinical bleeding (e.g., gastrointestinal bleeding) 16. Malignant hypertension (systolic blood pressure \>200 mmHg, or diastolic blood pressure \>120 mmHg) 17. Life expectancy ≤ 6 months 18. Contraindications of 3 T MRI examination 19. Pregnant or lactating women 20. Have participated in another clinical trial within 3 months prior to the date of informed consent, or are participating in another clinical trial.

Locations (25)

Peking Union Medical College Hospital

Beijing, Beijing Municipality, China

Beijing Shunyi Hospital

Beijing, Beijing Municipality, China

Beijing Shijitan Hospital, Capital Medical University

Beijing, Beijing Municipality, China

The First Hospital of Tsinghua University

Beijing, Beijing Municipality, China

The second hospital of Baoding

Baoding, Hebei, China

Botou City Hospital

Botou, Hebei, China

Cangzhou Central Hospital

Cangzhou, Hebei, China

Chengde Central Hospital

Chengde, Hebei, China

Affiliated Hospital of Chifeng University

Chifeng, Hebei, China

Hengshui People's Hospital

Hengshui, Hebei, China

...and 15 more locations

Outcomes

Primary Outcomes

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.

Time frame: 90 days

Secondary Outcomes

Excellent functional outcome

modified Rankin Scale score: 0-1

Time frame: 7 days

mRS

The modified Rankin Scale (mRS) is a commonly used 7-point ordinal scale ranging from 0 (no symptoms) to 6 (death), used to measure the degree of dependence in daily activities among patients with stroke or other neurological disabilities. The distribution of mRS scores at 7 and 90 days will be compared between the two study groups as an ordinal outcome, with higher scores indicating worse outcomes.

Time frame: 7 and 90 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.

Time frame: 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.

Time frame: 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.

Time frame: 90 days

Ischemic stroke

Number of participants with new-onset ischemic stroke, confirmed by senior neurologists and the Clinical Event Committee.

Time frame: 90 days

Stroke

Number of participants with new-onset ischemic or hemorrhagic stroke, confirmed by senior neurologists and the Clinical Event Committee.

Time frame: 90 days

TIA

Number of participants with new-onset transient ischemic attack (TIA), confirmed by senior neurologists and the Clinical Event Committee.

Time frame: 90 days

Composite endpoint

Number of participants with new-onset stroke, myocardial Infarction, or all-cause death, confirmed by the Clinical Event Committee.

Time frame: 90 days

Proportion of Major bleeding

Proportion of major bleeding defined by the PLATO criteria.

Time frame: 7 days and 90 days

Serious adverse events

Time frame: 90 days

Adverse events

Time frame: 90 days

All-cause death

Time frame: 90 days

Changes in hemoglobin

Blood test of the count of hemoglobin, g/L

Time frame: 48 hours

Changes in the count of red blood cell

Blood test of the count of red blood cell, 10\^12/L

Time frame: 48 hours

Changes in the count of white blood cell

Blood test of the count of white blood cell, 10\^9/L

Time frame: 48 hours

Changes in the count of platelets

Blood test of the count of platelets, 10\^9/L

Time frame: 48 hours

Changes in alanine transaminase

Serum biochemical test for alanine transaminase

Time frame: 48 hours

Changes in aspartate aminotransferase

Serum biochemical test for aspartate aminotransferase

Time frame: 48 hours

Changes in direct bilirubin

Serum biochemical test for the concentration of direct bilirubin

Time frame: 48 hours

Changes in indirect bilirubin

Serum biochemical test for the concentration of indirect bilirubin

Time frame: 48 hours

Changes in concentration of Na

Serum biochemical test for the concentration of sodium, mmol/L

Time frame: 48 hours

Changes in the concentration of K

Serum biochemical test for the concentration of potassium, mmol/L

Time frame: 48 hours

Changes in the concentration of creatinine

Serum biochemical test for creatinine

Time frame: 48 hours

Changes in the concentration of albumin

Serum biochemical test for albumin

Time frame: 48 hours

Changes in the urinary occult blood

The test of urine blood (BLD). Negative or positive.

Time frame: 48 hours

Changes in the fecal occult blood

The test of occult blood (Occult blood, OB). Negative or positive

Time frame: 48 hours

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

Overview

Conditions

Interventions

Eligibility

Locations (25)

Outcomes

Primary Outcomes

Secondary Outcomes