Clinical trial NCT05310968: Study on Tirofiban With Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction
Official title: Study on Tirofiban With Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction: A Randomized, Double-blinded, Placebo-controlled, Multi-center Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Branch Atheromatous Disease
Keywords: branch atheromatous disease
perforating artery territorial infarction
tirofiban
aspirin
randomized controlled trial
multicenter study
double blind study
placebo-controlled
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: GrandPharma (China) Co., Ltd.
First posted: 2022-04-05
Enrollment: 970
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: 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: 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:

1. Tirofiban (Day 1) + Aspirin (Day 1-90)
2. 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.

Eligibility criteria: Inclusion Criteria:

1. 18-80 years old;
2. No gender limitation;
3. Within 48 hours of onset;
4. Clinical symptoms and signs suggest acute single infarction of penetrating artery territory (no cortical involvement, no multifocal involvement, NIHSS ≤10 and consciousness-1a ≤1);
5. 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;
6. No severe stenosis (defined as \> 70%) of parent artery giving off the responsible penetrating artery;
7. The patient or his / her legal representative is able and willing to sign the informed consent.

Exclusion Criteria:

1. History of intracranial hemorrhage (subarachnoid hemorrhage and cerebral hemorrhage);
2. History of intracranial tumors, cerebral arteriovenous malformation, or aneurysm;
3. Emergency endovascular intervention or intravenous thrombolysis before randomization;
4. Dual antiplatelet therapy currently or within 14 days of randomization (excluding use of aspirin and clopidogrel after onset without loading dose of clopidogrel);
5. Use of other antiplatelet drugs (ticagrelor, cilostazol, etc.), anticoagulant drugs, snake venom, defibrase, lumbrukinase or other defibrase treatments after onset;
6. Expected long-term use of non-investigational antiplatelet drugs or non-steroidal anti-inflammatory drugs;
7. With severe stenosis (\> 70%) of parent artery giving off responsible penetrating artery;
8. 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);
9. 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);
10. 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;
11. Resistant hypertension which could not be controlled by medicine (SBP \> 180mmHg or DBP \> 110mmHg);
12. History of obvious head trauma or stroke within three months of randomization;
13. History of intracranial or intramedullary surgery within three months of randomization;
14. History of major surgery or severe physical trauma within one month of randomization;
15. Severe neurological defects (mRS ≥ 2) before the onset;
16. Acute pericarditis;
17. Hemorrhagic retinopathy;
18. Childbearing-age women who do not take effective methods of contraception without negative records of pregnancy tests;
19. Known to be allergic to tirofiban;
20. Other surgical or interventional therapy planned within 3 months requiring experimental drugs discontinuation;
21. Life expectancy \< 6 months due to any terminal illness;
22. Patients who are undergoing experimental drugs or instruments;
23. 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.

Primary outcomes:
measure: Number of participants with new stroke
timeFrame: 90 days after randomization
measure: Number of participants with early progression of stroke
timeFrame: 7 days after randomization
Secondary outcomes:
measure: Number of participants with new stroke or stroke progression
timeFrame: 24 hours and 7 days after randomization
measure: Number of participants with composite vascular events
timeFrame: 90 days after randomization
measure: Number of participants with disability or death
timeFrame: 90 days after randomization
measure: Number of participants with improvement of neurological function
timeFrame: 24 hours, 7 days, and 90 days after randomization
measure: EuroQol five dimensions questionnaire (EQ-5D)
timeFrame: 90 days after randomization
Other outcomes:
measure: Number of participants with severe hemorrhage events
timeFrame: 90 days after randomization
measure: Number of participants with symptomatic intracranial hemorrhage
timeFrame: 90 days after randomization
measure: Number of participants with symptomatic and non-symptomatic intracranial hemorrhage
timeFrame: 90 days after randomization
measure: Number of participants with moderate hemorrhage events
timeFrame: 90 days after randomization
measure: Number of participants with vascular death
timeFrame: 90 days after randomization
measure: Overall mortality
timeFrame: 90 days after randomization
measure: Number of participants with dverse event/serious adverse event
timeFrame: 90 days after randomization
Locations:
city: Beijing
country: China
facility: Beijing Hospital
state: Beijing
city: Zhangzhou
country: China
facility: The Affiliated Dongnan Hospital of Xiamen University
state: Fujian
city: Hejian
country: China
facility: Hejian People's Hospital
state: Hebei
city: Xingtai
country: China
facility: The People's Hospital of Qinghe County
state: Hebei
city: Henan
country: China
facility: Mengzhou People's Hospital
state: Henan
city: Jiaozuo
country: China
facility: The People's Hospital of Xiuwu County
state: Henan
city: Jiyuan
country: China
facility: Traditional Chinese Medicine Hospital of Jiyuan City
state: Henan
city: Nanyang
country: China
facility: The First People's Hospital of Nanyang
state: Henan
city: Nanyang
country: China
facility: The People's Hospital of Tanghe County
state: Henan
city: Shangqiu
country: China
facility: Traditional Chinese Medicine Hospital of Sui County
state: Henan
city: Zhumadian
country: China
facility: The People's Hospital of Biyang County
state: Henan
city: Shaoyang
country: China
facility: Shaodong People's Hospital
state: Hunan
city: Nantong
country: China
facility: The Third People's Hospital of Tongzhou District, Nantong City
state: Jiangsu
city: Xianyang
country: China
facility: The First People's Hospital of Xianyang
state: Shaanxi
city: Liaocheng
country: China
facility: Liaocheng Central Hospital
state: Shandong
city: Liaocheng
country: China
facility: The People's Hospital of Guan County
state: Shandong
city: Liaocheng
country: China
facility: The Third People's Hospital of Liaocheng
state: Shandong
city: Weihai
country: China
facility: Weihai Wendeng District People's Hospital
state: Shandong
city: Changzhi
country: China
facility: Changzhi People's Hospital
state: Shanxi
city: Yuncheng
country: China
facility: The People's Hospital of Wanrong County
state: Shanxi
Study officials:
affiliation: Beijing Tiantan Hospital, Capital Medical University, Beijing, China
name: Yilong Wang, PhD，MD
role: PRINCIPAL_INVESTIGATOR
References: