Tenecteplase for Late-Window Stroke Guided by DWI-FLAIR Mismatch (TRUST-MISMATCH)

Tenecteplase Thrombolysis for Acute Ischemic Stroke in the 4.5-9-Hour Window Guided by DWI-FLAIR Mismatch: A Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

The goal of this clinical trial is to evaluate the efficacy and safety of tenecteplase administered 4.5-9 hours after stroke onset (defined as the time the patient was first found with symptoms, including wake-up stroke and unwitnessed stroke) in patients with acute ischemic stroke (AIS) guided by DWI-FLAIR mismatch on MRI. The main questions it aims to answer are:

1. Does tenecteplase improve functional outcomes at 90 days compared with standard treatments in AIS patients administered 4.5-9 hours after stroke onset guided by DWI-FLAIR mismatch?
2. The safety of tenecteplase thrombolysis for AIS patients in the 4.5-9 hours guided by DWI-FLAIR mismatch.

Researchers will compare tenecteplase to placebo to see if it is effective and safe for these patients.

Participants will be randomly assigned (1:1) immediately after randomization:

• Tenecteplase group: received tenecteplase, intravenously as a bolus administered over a period of 5 to 10 seconds at a dose of 0.25 mg per kilogram (maximum dose, 25 mg), plus aspirin placebo (300 mg).
• Control group: aspirin (300 mg) plus tenecteplase placebo. From day 2 to day 90, all patients will be conformed to the 2023 Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: TNK-tPA; Drug: Placebo; Drug: Placebo; Drug: Aspirin

Detailed Description

Current clinical guidelines recommend intravenous thrombolysis (IVT) for eligible AIS patients within 4.5 hours of symptom onset. However, approximately 67 to 75% of patients present after 4.5 hours after stroke onset or with an unknown time of onset. CT perfusion (CTP) and perfusion-diffusion magnetic resonance imaging (MRI) have demonstrated that potentially viable brain tissue may persist beyond 4.5 hours after stroke onset. Recent trials, such as EXTEND, TRACE III, and the HOPE study, suggest that IVT can improve functional outcomes in AIS patients with salvageable brain tissue identified beyond 4.5 hours and up to 24 hours, using advanced perfusion imaging. Nonetheless, due to the high cost of perfusion software in developing countries, extended-window thrombolysis has not been widely implemented in many stroke centers. Therefore, it is crucial to develop alternative strategies to guide IVT in patients beyond 4.5 hours.

In recent years, the mismatch between a visible acute ischemic lesion on diffusion-weighted imaging (DWI) and the absence of a corresponding hyperintensity on fluid-attenuated inversion recovery (FLAIR) has been recognized as a predictor of symptom onset within 4.5 hours before imaging. The WAKE-UP trial demonstrated that among AIS patients with unknown time of onset (last known well >4.5 hours) and DWI-FLAIR mismatch, IVT administered within 4.5 hours after symptom recognition significantly improved functional outcomes. However, approximately 30% of AIS patients exhibit DWI-FLAIR mismatch between 4.5 and 9 hours after onset. Whether these patients can benefit from thrombolysis remains uncertain.

TRUST-MISMATCH is a multicenter, prospective, randomized, double-blind, placebo-controlled clinical. We want to evaluate the efficacy and safety of tenecteplase administered 4.5-9 hours after stroke onset (defined as the time the patient was first found with symptoms, including wake-up stroke and unwitnessed stroke) in AIS patients guided by DWI-FLAIR mismatch on MRI.

• Study Type: Interventional
• Enrollment (Estimated): 564
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bo Song, MD; Phone Number: +86-371-66278068; Email: fccsongb@zzu.edu.cn

Study Locations

• China
  • Henan
    • Zhengzhou, Henan, China, 450052
      • The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan
      • Contact: Bo Song, MD; Phone Number: +86-371-66278068; Email: fccsongb@zzu.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥ 18 years;
2. AIS with symptom onset 4.5-9 hours before enrollment, including wake-up stroke and unwitnessed stroke (onset time defined as when symptoms were first noticed);

3. Imaging criteria:

   1. DWI-FLAIR mismatch: visible lesion on DWI with no marked visible lesion on FLAIR;
   2. DWI infarct core not exceeding one-third of the middle cerebral artery territory, one-half of the anterior cerebral artery territory, or one-half of the posterior cerebral artery territory;
4. NIHSS score 4-25;
5. First-ever stroke or previous stroke without significant disability (pre-stroke mRS ≤ 1);
6. Signed informed consent from the patient or legally authorized representative.

Exclusion Criteria:

1. Planned endovascular treatment;
2. Contradictory to MRI examination;
3. MRI image not qualified for evaluation;
4. Serious neurological deficits before onset (mRS≥2);
5. Obvious head injuries or strokes within 3 months;
6. Subarachnoid or intracranial hemorrhage;
7. History of intracranial hemorrhage;
8. Intracranial tumor, arteriovenous malformation or aneurysm;
9. Intracranial or spinal cord surgery within 3 months;
10. Active internal hemorrhage;
11. platelet count of <100000/mm3;
12. Aortic arch dissection;
13. Heparin therapy within 24 hours;
14. Oral warfarin is being taken and INR>1.6 or APTT abnormal;
15. Oral anticoagulation therapy;
16. Systolic pressure≥185 mmHg or diastolic pressure≥110 mmHg;
17. Blood glucose < 50 mg/dl (2.7mmol/L);
18. Pregnancy;
19. Neurological deficit after epileptic seizures;
20. Major surgery within 1 month;
21. Gastrointestinal or urinary tract hemorrhage within the previous 30 days;
22. Myocardial infarction within 3 months;
23. Allergy to study drugs;
24. Unlikely to adhere to the trial protocol or follow-up;
25. Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study;
26. Participation in other interventional clinical trials within the previous 3 months.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tenecteplase group: Patients will receive tenecteplase, intravenously as a bolus administered over a period of 5 to 10 seconds at a dose of 0.25 mg per kilogram (maximum dose, 25 mg), plus aspirin placebo (300 mg) immediately after randomization.From day 2 to day 90, all patients will be conformed to the 2023 Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke.	Drug: TNK-tPA; TNK-tPA (0.25 mg/kg, to maximum of 25mg); Drug: Placebo; Asprin (placebo); Drug: Placebo; TNK-tPA (placebo)
Active Comparator: Control group; Patients will receive asprin(300mg) plus intravenous TNK(placebo, 0.25mg/kg, a maximum of 25 mg) immediately after randomization. From day 2 to day 90, patients will be conformed to the 2023 Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke.	Drug: Placebo; Asprin (placebo); Drug: Placebo; TNK-tPA (placebo); Drug: Aspirin; Asprin (300mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)	Proportion of subjects of excellent outcome defined as mRS (0-1) at 90 ± 7 days.	90 ± 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)	Proportion of subjects of excellent outcome defined as mRS (0-2) at 90 ± 7 days.	90 ± 7 days
Modified Rankin Scale (mRS)	Ordinal shift analysis of mRS at 90 days	90 ± 7 days
National Institutes of Health Stroke Scale (NIHSS)	NIHSS change from baseline at 24 hours and 7 days.	24 hours and 7 days
Barthel (BI)	Barthel Index score at 90 ± 7 days.	90 ± 7 days
EuroQol 5-Dimension (EQ-5D)	Quality of life measured by EQ-5D scale at 90 ± 7 days.	90 ± 7 days
Modified Rankin Scale (mRS)	Proportion of subjects of excellent outcome defined as mRS (0-2) at 90 ± 7 days.; Ordinal distribution of mRS at 90 ± 7 days	90 ± 7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Overall mortality rate at 90 days.	90 days
Symptomatic intracranial hemorrhage (sICH)	Proportion of subjects with symptomatic intracranial hemorrhage (sICH) at 36 hours (according to the ECASS III criteria).	36 hours
Systemic bleeding	Systemic bleeding at 90 days (according to the GUSTO criteria)	90 days
Adverse events (AEs)/ serious adverse events (SAEs)	Proportion of patients with adverse events (AEs)/ serious adverse events (SAEs) within 90 days.	90 days

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Zhengzhou University
• Investigators: Study Chair: Bo Song, MD, Department of Neurology, the First Affiliated Hospital of Zhengzhou University

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: April 6, 2026
• First Submitted That Met QC Criteria: April 17, 2026
• First Posted (Actual): April 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 20, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Thrombolysis; diffusion weighted imaging; Tenecteplase; fluid attenuated inversion recovery
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Phenols; Benzene Derivatives; Salicylates; Hydroxybenzoates; Aspirin; TNK-tissue plasminogen activator
• Other Study ID Numbers: MISMATCH-001

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