Tirofiban for the Prevention of Early Neurological Deterioration After Intravenous Thrombolysis in Acute Ischemic Stroke (TREND-2)

Effects of Tirofiban on Early Neurological Deterioration After Intravenous Thrombolysis in Patients with Acute Ischemic Stroke: an Open-label, Multicenter, Randomized Controlled Trial

A prospective, multicenter, randomized, controlled, open-label, blinded endpoint trial to evaluate the safety and efficacy of intravenous administration of tirofiban for preventing early neurological deterioration after intravenous thrombolysis in patients with acute ischemic stroke.

Study Overview

• Status: Not yet recruiting
• Conditions: Cerebral Infarction; Acute Stroke; Ischemic Stroke, Acute
• Intervention / Treatment: Drug: Tirofiban Hydrochloride; Drug: Standard medical treatment (SMT)

Detailed Description

Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA), administered within 4.5 hours of symptom onset, remains the standard treatment strategy for acute ischemic stroke. However, approximately 6-40% of patients experienced early neurological deterioration following intravenous thrombolysis, among which more than 70% resulted from ischemic events, with 20-34% due to early re-occlusion of the recanalized artery. Augmented platelet activation, triggered by the activated coagulation cascade and endothelial injury during rt-PA administration, is recognized as one of the primary reasons for ischemic events after intravenous thrombolysis. Early antiplatelet therapy following rt-PA effectively reduces neurological deterioration and improves functional outcomes. However, the current guidelines recommend that antiplatelet therapy should be initiated 24 hours after intravenous thrombolysis due to the potential risk of intracerebral hemorrhage.

Tirofiban, a glycoprotein (GP) IIb/IIIa receptor inhibitor renowned for its rapid action, high selectivity, and short half-life, has been found to exert a remarkable antiplatelet effect by effectively blocking the terminal pathway that triggers platelet aggregation. One recent randomized trial found that among patients with acute non-cardioembolic ischemic stroke who presented within 24 hours of symptom onset, intravenous tirofiban resulted in a lower likelihood of early neurological deterioration than oral aspirin, without increasing the risk of intracranial hemorrhage or systematic bleeding. Another randomized trial found that treatment with intravenous tirofiban administration was safe and significantly improved 3-month functional outcomes in patients who experienced early neurological deterioration or no improvement within 24 hours of intravenous thrombolysis, compared with aspirin. Furthermore, our previous study found that early administration of tirofiban in patients with early neurological deterioration within the first 24 hours of intravenous thrombolysis did not increase the risk of symptomatic intracerebral hemorrhage, any intracerebral hemorrhage, or mortality. In contrast, it was associated with neurological improvement at 3 months. However, whether early administration of tirofiban can safely and effectively prevent neurological deterioration in patients with acute ischemic stroke treated with intravenous thrombolysis within 24 hours remains unclear, while the subset of patients who may benefit from early antiplatelet therapy.

• Study Type: Interventional
• Enrollment (Estimated): 302
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: XunMing Ji, MD, PD; Phone Number: 86-10-8319-9439; Email: jixm@ccmu.edu.cn
• Study Contact Backup: Name: Wenbo Zhao, MD, PD; Phone Number: 86-10-8319-9048; Email: zhaowb@xwh.ccmu.edu.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100053
      • Xuanwu Hospital, Capital Medical University
      • Contact: Wenbo Zhao, MD, PD; Phone Number: 010-8319-9048; Email: zhaowb@xwh.ccmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years old;
2. Acute ischemic stroke treated with intravenous thrombolysis with alteplase or tenecteplase within 4.5 hours of onset or time last known well and can receive the study drug treatment within 3 hours of initiating intravenous thrombolysis.
3. Residual NIHSS score ≥ 5 points at randomization (at least 1 hour after intravenous thrombolytic therapy).
4. Post-thrombolysis imaging shows that the offending artery is consistent with moderate or severe intracranial atherosclerotic stenosis (within 50%~99%)
5. Informed consent obtained from patients or their acceptable surrogates.

Exclusion Criteria:

1. Intracranial hemorrhage confirmed by imaging post-thrombolysis.
2. Stroke caused by other determined causes, including moyamoya disease, artery dissection, arteritis, etc.
3. Scheduled for or received endovascular treatment after onset.
4. Definite or suspected cardioembolic stroke.
5. Definite anticipation of developing indications for anticoagulant therapy during the study period (e.g., atrial fibrillation, mechanical heart valve, deep vein thrombosis, pulmonary embolism, antiphospholipid syndrome, hypercoagulable state).
6. Use of antiplatelet or anticoagulant therapy within one week pre-stroke.
7. Pre-stroke mRS score ≥ 2.
8. Severe consciousness disturbance with NIHSS item 1a (level of consciousness) >1 point at randomization.
9. History of tirofiban allergy or its solvents.
10. History of platelet count < 100 × 109/L caused by tirofiban.
11. Major surgical operation within 6 weeks.
12. Major systemic hemorrhage within 30 days;
13. Determined coagulation disorders, platelet dysfunction, or platelet count < 100*109/L.
14. Currently pregnant or lactating;
15. Uncontrolled hypertension with systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg.
16. Acute pericarditis or hemorrhagic retinopathy.
17. Presence of malignant tumors, chronic hemodialysis, severe renal insufficiency (GFR < 30 ml/min or serum Cr > 220 μmol/L (2.5 mg/dl)), severe hepatic insufficiency (serum ALT > 2 times the upper limit of normal, or serum AST > 2 times the upper limit of normal), severe heart failure (NYHA class III or IV).
18. Severe non-cardiovascular complications with an expected survival of less than 6 months.
19. Unavailability for follow-up.
20. Presence of dementia, psychiatric disorders, or other known neurological conditions that complicate follow-up.
21. Participated in this study in the past.
22. Current participation in another therapeutic study with ongoing treatment and follow-up.
23. Other conditions that are not suitable for participation in this study as determined by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirofiban Group; Patients will receive tirofiban in the first 24 hours after intravenous thrombolysis, then bridge to oral antiplatelet therapy.	Drug: Tirofiban Hydrochloride; Tirofiban will use a loading dose, 0.4 μg/kg/min × 30 minutes, then 0.1μg/kg/min infusion until 24 hours after Intravenous thrombolytic therapy, or use a loading dose, 25 μg/kg, administrated within 3 minutes, then 0.15μg/kg/min infusion until 24 hours after Intravenous thrombolytic therapy.
Active Comparator: Control group; Aspirin, clopidogrel, or other antiplatelet drugs will be used in principle after 24 hours of thrombolytic therapy or until the primary outcome occurs.	Drug: Standard medical treatment (SMT); Patients will receive standard antiplatelet therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients experiencing neurological deterioration within 24 hours after intravenous thrombolysis.	National Health Institute Stroke Scale (NIHSS): stroke symptom severity scale ranging from 0-42. A higher score means more severe stroke symptoms. Neurological deterioration is defined as an increase in NIHSS by ≥ 4 points compared to the lowest NIHSS.	Within 24 hours after intravenous thombolysis.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of the NIHSS	National Health Institute Stroke Scale (NIHSS): stroke symptom severity scale with a range of 0-42. Higher score means more severe stroke symptoms.	7 days or discharge after intravenous thrombolytic therapy
The proportion of patients with a modified Rankin scale (mRS) score of 0-1 at 30-day follow up.	The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels, which ranging from 0 (no symptom) to 5 (severe disability) and 6 (death).	30 days after stroke
The proportion of patients with a modified Rankin scale (mRS) score of 0-1 at 90-day follow up.	The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels, which ranging from 0 (no symptom) to 5 (severe disability) and 6 (death).	90 days after stroke
The proportion of patients with a modified Rankin scale (mRS) score of 0-2 at 30-day follow up.	The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels, which ranging from 0 (no symptom) to 5 (severe disability) and 6 (death).	30 days after stroke
The proportion of patients with a modified Rankin scale (mRS) score of 0-2 at 90-day follow up.	The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels, which ranging from 0 (no symptom) to 5 (severe disability) and 6 (death).	90 days after stroke
Distribution of modified Rankin Scale (mRS) scores at 90 day.	The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels, which ranging from 0 (no symptom) to 5 (severe disability) and 6 (death).	90 days after stroke
Incidence of symptomatic intracranial hemorrhage within 24 hours of intervention.	Symptomatic intracranial hemorrhage is defined as the demonstration of hemorrhage within brain parenchyma on head imaging leading to an increase of at least 4 points in the NIHSS score, according to the criteria of the European Cooperative Acute Stroke Study III (ECASS III).	Within 24 hours of intervention
Incidence of any intracranial hemorrhage within 24 hours of intervention.	Any intracranial hemorrhage is defined as the demonstration of hemorrhage within brain parenchyma on head imaging, according to the criteria of the ECASS III.	Within 24 hours of intervention
Incidence of systemic hemorrhage within 90 days after stroke.	The incidence of systemic hemorrhage at any time from randomization through day 90, according to the criteria of the GUSTO.	Within 90 days after stroke.
Incidence of recurrent stroke or other vascular events within 90 days after stroke.	The incidence of recurrent stroke or other vascular events (including hemorrhagic and ischemic stroke, myocardial infarction, and cardiovascular death) within 90 days of randomization.	Within 90 days after stroke.
All-cause death within 90 days after stroke.	The incidence of death events at any time from randomization through day 90.	Within 90 days after stroke.
Incidence of Adverse Events/Serious Adverse Events within 90 days after stroke.	The incidence of other adverse events and serious adverse events at any time from randomization through day 90.	Within 90 days after stroke.
Proportion of patients experiencing neurological deterioration (an increase in NIHSS by ≥ 2 points compared to the lowest NIHSS) within 24 hours after intravenous thrombolysis.	National Health Institute Stroke Scale (NIHSS): stroke symptom severity scale with a range of 0-42. Higher score means more severe stroke symptoms.	Within 24 hours of intravenous thrombolysis.
Proportion of patients experiencing neurological deterioration (an increase in NIHSS by ≥ 4 points compared to the lowest NIHSS) within 48 hours after intravenous thrombolysis.	National Health Institute Stroke Scale (NIHSS): stroke symptom severity scale with a range of 0-42. Higher score means more severe stroke symptoms.	Within 48 hours after intravenous thrombolysis.
Proportion of patients experiencing (an increase in NIHSS by ≥ 4 points compared to the lowest NIHSS) within 72 hours after intravenous thrombolysis.	National Health Institute Stroke Scale (NIHSS): stroke symptom severity scale with a range of 0-42. Higher score means more severe stroke symptoms.	Within 72 hours after intravenous thrombolysis.
Proportion of patients experiencing neurological deterioration (an increase in NIHSS by ≥ 4 points compared to the lowest NIHSS) within 7 days after intravenous thrombolysis.	National Health Institute Stroke Scale (NIHSS): stroke symptom severity scale with a range of 0-42. Higher score means more severe stroke symptoms.	Within 7 days after intravenous thrombolysis.
Proportion of patients with a decrease in NIHSS by ≥ 2 points compared to NIHSS at randomization.	National Health Institute Stroke Scale (NIHSS): stroke symptom severity scale with a range of 0-42. Higher score means more severe stroke symptoms.	24 hours after intravenous thrombolysis.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers levels of groups	The biomarkers include CLEC2, CD62P, TXB2, 6-k-PGFla, EETs, 20-HETE, BCAA, ALDH2	Within 24 hours of intervention

Collaborators and Investigators

• Sponsor: Capital Medical University

Publications and helpful links

General Publications

• Wu C, Sun C, Wang L, Lian Y, Xie N, Huang S, Zhao W, Ren M, Wu D, Ding J, Song H, Wang Y, Ma Q, Ji X. Low-Dose Tirofiban Treatment Improves Neurological Deterioration Outcome After Intravenous Thrombolysis. Stroke. 2019 Dec;50(12):3481-3487. doi: 10.1161/STROKEAHA.119.026240. Epub 2019 Oct 1.
• Zhao W, Li S, Li C, Wu C, Wang J, Xing L, Wan Y, Qin J, Xu Y, Wang R, Wen C, Wang A, Liu L, Wang J, Song H, Feng W, Ma Q, Ji X; TREND Investigators. Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. 2024 Jun 1;81(6):594-602. doi: 10.1001/jamaneurol.2024.0868. Erratum In: JAMA Neurol. 2024 Aug 1;81(8):889. doi: 10.1001/jamaneurol.2024.2195.
• Zi W, Song J, Kong W, Huang J, Guo C, He W, Yu Y, Zhang B, Geng W, Tan X, Tian Y, Liu Z, Cao M, Cheng D, Li B, Huang W, Liu J, Wang P, Yu Z, Liang H, Yang S, Tang M, Liu W, Huang X, Liu S, Tang Y, Wu Y, Yao L, Shi Z, He P, Zhao H, Chen Z, Luo J, Wan Y, Shi Q, Wang M, Yang D, Chen X, Huang F, Mu J, Li H, Li Z, Zheng J, Xie S, Cai T, Peng Y, Xie W, Qiu Z, Liu C, Yue C, Li L, Tian Y, Yang D, Miao J, Yang J, Hu J, Nogueira RG, Wang D, Saver JL, Li F, Yang Q; RESCUE BT2 Investigators. Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion. N Engl J Med. 2023 Jun 1;388(22):2025-2036. doi: 10.1056/NEJMoa2214299.

Study record dates

Study Major Dates

• Study Start (Estimated): November 20, 2024
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: August 30, 2024
• First Submitted That Met QC Criteria: September 5, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): October 29, 2024
• Last Update Submitted That Met QC Criteria: October 28, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Acute ischemic stroke; Antiplatelet therapy; Neurological deterioration; intravenous thrombolysis; Stroke progression
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Brain Infarction; Brain Ischemia; Necrosis; Ischemic Stroke; Stroke; Cerebral Infarction; Ischemia; Infarction; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Fibrinolytic Agents; Platelet Aggregation Inhibitors; Tirofiban
• Other Study ID Numbers: TREND-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No