Branch Atheromatous Disease
Conditions
Keywords
Branch atheromatous disease, Tirofiban, Stroke, Treatment Outcome, Magnetic Resonance Imaging
Brief summary
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
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.
Interventions
DRUGTirofiban
Tirofiban, a GPIIb/IIIa receptor inhibitor. Intravenous administration.
DRUGAspirin tablet
Aspirin. Oral administration.
Clopidogrel. Oral administration.
Sponsors
Peking Union Medical College Hospital
Pharmaron (Chengdu) Clinical Services Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Our study is an open label, blinded endpoint trail. The primary outcome should be measured in a blinded manner, and the qualified evaluator is defined as: 1) Attending neurologists or above; 2) Complete the training for mRS score before the initiation of patient enrollment; 3) Blind to the antiplatelet treatment of the participants; and 4) Sign the evaluation when it is completed, and inform the other investigators of the results. All the clinical and safety events will be re-examined by the independent Clinical Event Committee (CEC), who are blinded during all procedures.
Intervention model description
multi-center, randomized, open label, blinded endpoint, parallel controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Excellent functional outcome | 90 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in the count of white blood cell | 48 hours | Blood test of the count of white blood cell, 10\^9/L |
| Changes in the count of platelets | 48 hours | Blood test of the count of platelets, 10\^9/L |
| Changes in alanine transaminase | 48 hours | Serum biochemical test for alanine transaminase |
| Changes in aspartate aminotransferase | 48 hours | Serum biochemical test for aspartate aminotransferase |
| Changes in direct bilirubin | 48 hours | Serum biochemical test for the concentration of direct bilirubin |
| Changes in indirect bilirubin | 48 hours | Serum biochemical test for the concentration of indirect bilirubin |
| Changes in concentration of Na | 48 hours | Serum biochemical test for the concentration of sodium, mmol/L |
| Changes in the concentration of K | 48 hours | Serum biochemical test for the concentration of potassium, mmol/L |
| Changes in the concentration of creatinine | 48 hours | Serum biochemical test for creatinine |
| Changes in the concentration of albumin | 48 hours | Serum biochemical test for albumin |
| Changes in the urinary occult blood | 48 hours | The test of urine blood (BLD). Negative or positive. |
| Changes in the fecal occult blood | 48 hours | The test of occult blood (Occult blood, OB). Negative or positive |
| Excellent functional outcome | 7 days | modified Rankin Scale score: 0-1 |
| mRS | 7 and 90 days | 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. |
| Early neurological deterioration | 7 days of randomization | 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. |
| NIHSS score | 7 days and 90 days | 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. |
| Barthel index score | 90 days | 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. |
| Ischemic stroke | 90 days | Number of participants with new-onset ischemic stroke, confirmed by senior neurologists and the Clinical Event Committee. |
| Stroke | 90 days | Number of participants with new-onset ischemic or hemorrhagic stroke, confirmed by senior neurologists and the Clinical Event Committee. |
| TIA | 90 days | Number of participants with new-onset transient ischemic attack (TIA), confirmed by senior neurologists and the Clinical Event Committee. |
| Composite endpoint | 90 days | Number of participants with new-onset stroke, myocardial Infarction, or all-cause death, confirmed by the Clinical Event Committee. |
| Proportion of Major bleeding | 7 days and 90 days | Proportion of major bleeding defined by the PLATO criteria. |
| Serious adverse events | 90 days | Serious adverse events |
| Adverse events | 90 days | Adverse events |
| All-cause death | 90 days | All-cause death |
| Changes in the count of red blood cell | 48 hours | Blood test of the count of red blood cell, 10\^12/L |
| Changes in hemoglobin | 48 hours | Blood test of the count of hemoglobin, g/L |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORJun Ni, MD
The office for BRANT study
Outcome results
None listed