A Multicenter, Three-Arm, Open-Label, Endpoint-Blinded Randomized Controlled Trial to Evaluate the Optimal Duration of Early Tirofiban After Intravenous Thrombolysis in Acute Ischemic Stroke (INSTANT-2)

A Multicenter, Three-Arm, Open-Label, Endpoint-Blinded Randomized Controlled Trial to Evaluate the Optimal Infusion Duration of Early Tirofiban Treatment After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke (INSTANT-2)

Acute ischemic stroke is a leading cause of disability and mortality among dults in China. Although intravenous thrombolysis serves as first-line reperfusion therapy, nearly half of patients fail to achieve vascular recanalization. The reocclusion rate ranges from 14% to 34%, and many patients are left with residual neurological deficits. Early antiplatelet therapy initiated after thrombolysis may sustain persistent reperfusion and improve prognosis. However, current guidelines generally recommend delaying antiplatelet treatment until 24 hours post-thrombolysis due to bleeding risks, and direct evidence for the optimal initiation timing remains lacking. Tirofiban is a rapidly acting, short-half-life, reversible glycoprotein IIb/IIIa receptor antagonist. Previous studies indicate its potential benefits and acceptable safety when administered after intravenous thrombolysis.

This is a multicenter, three-arm, open-label, endpoint-blinded randomized controlled trial. A total of 1482 non-cardioembolic patients without large or medium vessel occlusion and with residual neurological deficits (NIHSS ≥4) after thrombolysis will be enrolled. Participants will be randomly allocated to the tirofiban 24-hour group, tirofiban 48-hour group, or blank control group. The primary outcome is the proportion of patients with excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 90 days. Symptomatic intracranial hemorrhage and neurological outcomes will also be evaluated. The study aims to determine the optimal duration of tirofiban treatment after thrombolysis and provide high-level evidence for precise interventions in the acute phase of stroke.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: Tirofiban Injection; Drug: Tirofiban Injection; Other: No Interventions

• Study Type: Interventional
• Enrollment (Estimated): 1482
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Guoyong Zeng, doctor; Phone Number: +8613507079530; Email: hsyygy@126.com
• Study Contact Backup: Name: Fan Zhang, doctor; Phone Number: +8618970148470; Email: zhappy0066@126.com

Study Locations

• China
  • Anhui
    • Fuyang, Anhui, China, 236600
      • Taihe County People's Hospital
  • Fujian
    • Longyan, Fujian, China, 364000
      • Longyan First Hospital of Fujian Medical University
  • Hunan
    • Xiangtan, Hunan, China, 411100
      • Xiangtan Central Hospital (The Affiliated Hospital of Hunan University)
  • Jiangxi
    • Ganzhou, Jiangxi, China, 341000
      • Ganzhou People's Hospital
    • Ganzhou, Jiangxi, China, 342414
      • Xingguo People's Hospital, Xinguo Hospital of Gannan Medical University
    • Jingdezhen, Jiangxi, China, 333000
      • Jingdezhen First People's Hospital
    • Jingdezhen, Jiangxi, China, 341000
      • The First People's Hospital of Jingdezhen City
    • Jiujiang, Jiangxi, China
      • Jiujiang First People's Hospital
  • Liaoning
    • Dalian, Liaoning, China, 116000
      • Dalian Central Hospital
  • Sichuan
    • Mianyang, Sichuan, China, 621000
      • The First People's Hospital of Mianyang (Mianyang 404 Hospital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years.
2. Diagnosis of acute ischemic stroke meeting the diagnostic criteria from Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2023, and the patient has received intravenous thrombolysis with tenecteplase, alteplase or reteplase.
3. Disabling stroke remains at 2-24 hours after completion of intravenous thrombolysis. Disabling stroke is defined as NIHSS score ≥ 4, or single limb motor subscore ≥ 2.
4. Written informed consent is obtained from the patient or legal representative.

Exclusion Criteria:

1. Intracranial hemorrhage confirmed by CT or MRI after intravenous thrombolysis and prior to randomization.
2. CTA/MRA/DSA demonstrates occlusion of the internal carotid artery, M1 or M2 segment of the middle cerebral artery, anterior cerebral artery, or vertebrobasilar artery.
3. History of atrial fibrillation or suspected cardioembolic stroke. Platelet count <100×10⁹/L on routine blood test.
4. Renal insufficiency with estimated glomerular filtration rate (eGFR) <30 mL/min.
5. Pregnant or breastfeeding women.
6. Pre-existing neurological or psychiatric disorders that interfere with neurological function assessment.
7. History of bleeding disorders, severe cardiac, hepatic or renal disease, or sepsis.
8. Brain tumor with mass effect on imaging (excluding small meningioma). Intracranial aneurysm or arteriovenous malformation (AVM).
9. Advanced illness with life expectancy less than 6 months.
10. Current participation in another clinical trial.
11. Other conditions deemed unsuitable for enrollment by the investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Tirofiban 24-hour group; Arm A: Patients receive tirofiban for 24 hours after intravenous thrombolysis.	Drug: Tirofiban Injection; Intravenous infusion of tirofiban will be initiated after intravenous thrombolysis and continued for 24 hours. The dosage regimen follows the trial protocol.; Drug: Tirofiban Injection; Intravenous infusion of tirofiban will be initiated after intravenous thrombolysis and continued for 48 hours. The dosage regimen follows the trial protocol.
Experimental: Arm B: Tirofiban 48-hour group; Arm B: Patients receive tirofiban for 48 hours after intravenous thrombolysis.	Drug: Tirofiban Injection; Intravenous infusion of tirofiban will be initiated after intravenous thrombolysis and continued for 24 hours. The dosage regimen follows the trial protocol.; Drug: Tirofiban Injection; Intravenous infusion of tirofiban will be initiated after intravenous thrombolysis and continued for 48 hours. The dosage regimen follows the trial protocol.
Active Comparator: Arm C: Standard care control group; No tirofiban is administered after intravenous thrombolysis.	Other: No Interventions; No tirofiban will be administered after intravenous thrombolysis. Patients receive routine standard clinical management according to hospital guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with mRS 0-1 at 90 days	Percentage of participants achieving modified Rankin Scale (mRS) score 0 or 1 at 90 days after randomization.	90 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mRS score at 90 days	Modified Rankin Scale (mRS) score assessed at 90 days after randomization.	90 days after randomization
EQ-5D-5L score at 90 days	EQ-5D-5L questionnaire score assessed at 90 days after randomization.	90 days after randomization
Proportion of patients with mRS 0-2 at 90 days	Percentage of participants achieving modified Rankin Scale (mRS) score 0 to 2 at 90 days after randomization.	90 days after randomization
Proportion of patients with mRS 0-3 at 90 days	Percentage of participants achieving modified Rankin Scale (mRS) score 0 to 3 at 90 days after randomization.	90 days after randomization
Proportion of early neurological improvement	Percentage of participants with early neurological improvement, defined as ≥30% reduction in NIHSS score at 48 hours post-randomization compared with the NIHSS score at randomization.	48 hours after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of symptomatic intracranial hemorrhage (sICH) within 48 hours	Proportion of participants with symptomatic intracranial hemorrhage (sICH) within 48 hours after randomization, defined by the Heidelberg criteria.	Within 48 hours after randomization
Incidence of any intracranial hemorrhage (any ICH) within 48 hours	Proportion of participants with any intracranial hemorrhage (any ICH) within 48 hours after randomization.	Within 48 hours after randomization
90-day mortality	Proportion of participants who die within 90 days after randomization.	90 days after randomization

Collaborators and Investigators

• Sponsor: Xinqiao Hospital of Chongqing
• Collaborators: The Affiliated Ganzhou Hospital of Nanchang University
• Investigators: Principal Investigator: zhongming qiu, Xinqiao Hospital of the Army Medical University

Publications and helpful links

General Publications

• INSTANT Trial Authors for the INSTANT Investigators; Liu X, Zhang F, Zhang C, Li Z, Yuan G, Kong D, Xie S, Zhou M, Ye J, Lai Z, Li D, Xu H, Chen L, Cheng F, Shi Y, Chen B, Hu W, Liu H, Yin Y, Deng X, Xie Z, Li C, Shi J, Mei D, Liu B, Wang B, Zhou R, Liu J, Shen L, Hu H, Xiao G, Guan X, Yuan S, Lv X, Liang S, Zeng X, Chen Y, Cao W, Zheng C, Liu Y, Li J, Guan B, Lai T, Sun W, Zeng H, Zhang J, Li S, Sang H, Tang Y, Wang D, Lu M, Kaesmacher J, Yogendrakumar V, Pan S, Nogueira RG, Hong D, Goyal M, Thomalla G, Nguyen TN, Saver JL, Yang Q, Qiu Z, Zeng G. Intravenous Tirofiban After Tenecteplase in Acute Ischemic Stroke: The INSTANT Randomized Clinical Trial. JAMA. 2026 Jun 9;335(22):1949-1958. doi: 10.1001/jama.2026.5245.

Study record dates

Study Major Dates

• Study Start (Estimated): November 19, 2026
• Primary Completion (Estimated): December 30, 2030
• Study Completion (Estimated): May 8, 2031

Study Registration Dates

• First Submitted: September 20, 2026
• First Submitted That Met QC Criteria: September 20, 2026
• First Posted (Actual): September 25, 2026

Study Record Updates

• Last Update Posted (Actual): September 25, 2026
• Last Update Submitted That Met QC Criteria: September 20, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: acute ischemic stroke; tenecteplase; alteplase; tirofiban; Intravenous Thrombolysis
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke; Amino Acids, Peptides, and Proteins; Amino Acids; Amino Acids, Aromatic; Amino Acids, Cyclic; Tyrosine; Tirofiban
• Other Study ID Numbers: INSTANT-2

Plan for Individual participant data (IPD)

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

IPD Plan Description

De-identified cleaned individual participant data (IPD) will be shared upon reasonable request after publication of the primary study results. All personal identifiers will be removed to protect participant privacy.

IPD Sharing Time Frame

Available starting 6 months after publication of the primary manuscript.

IPD Sharing Access Criteria

Interested researchers may submit a formal research proposal and data access request to the corresponding author. The study steering committee will review each application.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No