Endovascular Treatment With or Without Preceding Intravenous Tenecteplase (TNK) in Patients With Late-window acUte Ischemic Stroke Due to Middle Cerebral Artery Occlusion (TNK-PLUS)

Endovascular Treatment With or Without Preceding Intravenous Tenecteplase (TNK) in Patients With Late-window acUte Ischemic Stroke Due to Middle Cerebral Artery Occlusion: a Multi-center, Prospective, Randomized, Open-label, Blinded Endpoint (PROBE), Phase 3 Trial

The purpose of this study is to investigate the safety and efficacy of endovascular treatment with or without preceding intravenous Tenecteplase in patients with late-window (4.5-24 hours of symptom onset) acute ischemic stroke due to middle cerebral artery (MCA) M1 or proximal M2 occlusion.

Study Overview

• Status: Completed
• Conditions: Thrombolysis; Ischemic Stroke, Acute; Endovascular Treatment
• Intervention / Treatment: Device: direct EVT; Drug: Tenecteplase

Detailed Description

After being informed about the study and potential risks, patients who meet the inclusion criteria will be randomized to endovascular treatment with preceding intravenous Tenecteplase (0.25mg/kg, maximum 25mg) or without preceding intravenous Tenecteplase in a 1:1 ratio. Written informed consent will be needed.

• Study Type: Interventional
• Enrollment (Actual): 391
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • The First Affiliated hospital of USTC
    • Wuhu, Anhui, China
      • First Affiliated Hospital of Wannan Medical College
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100070
      • Beijing Tiantan Hospital, Capital Medical University
    • Beijing, Beijing Municipality, China
      • Beijing Daxing District People'S Hospital
  • Heilongjiang
    • Harbin, Heilongjiang, China
      • The 2nd Affiliated Hospital of Harbin Medical University
  • Henan
    • Puyang, Henan, China
      • Puyang Oilfield General Hospital
    • Zhumadian, Henan, China
      • People's Hospital of Queshan
  • Hunan
    • Chenzhou, Hunan, China, 423000
      • First People's Hospital of Chenzhou
  • Liaoning
    • Dalian, Liaoning, China
      • Dalian Municipal Central Hospital
  • Shaanxi
    • Xi'an, Shaanxi, China, 710061
      • First Affiliated Hospital of Xi 'an Jiaotong University
  • Shandong
    • Heze, Shandong, China, 274400
      • Heze Municipal Hospital
    • Jining, Shandong, China
      • Jining No.1 People's Hospital
    • Liaocheng, Shandong, China, 252006
      • Liaocheng Third People's Hospital
    • Linyi, Shandong, China, 276003
      • Linyi People's Hospital
    • Linyi, Shandong, China
      • Linyi Central Hospital
    • Qingdao, Shandong, China, 266000
      • Qingdao Central Hospital
    • Rizhao, Shandong, China, 276800
      • Rizhao People's Hospital
    • Rizhao, Shandong, China, 276800
      • Rizhao traditional Chinese medicine hospital
    • Weifang, Shandong, China
      • Weifang People's Hospital
    • Zaozhuang, Shandong, China
      • Zaozhuang Municipal Hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Zhejiang Provincial People's Hospital

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 symptom onset between 4.5 to 24 hours prior to enrollment including wake-up stroke and unwitnessed stroke; onset time refers to 'last seen well time';
3. MCA-M1 or proximal M2 occlusions confirmed by Computer Tomography Angiography (CTA)/Magnetic Resonance Angiography (MRA) that was responsible for signs and symptoms of acute ischemic stroke;
4. Neuroimaging: target mismatch profile on CT perfusion (CTP) or MRI + MR perfusion imaging (MRP) (analyzed by perfusion analysis software with Class II and above medical device certificates) [ischemic core volume (defined as CBF<30% or apparent diffusion coefficient value < 620×10-6 mm2/s) <70mL, mismatch ratio≥1.8, mismatch volume≥15mL];
5. Pre-morbid mRS score ≤2;
6. Baseline NIHSS 6-25 (both included);
7. Written informed consent from patients or their legally authorized representative.

Exclusion criteria

1. Patients who decline interventional therapy or intravenous thrombolysis (IVT)；
2. Patients allergic to tenecteplase；
3. Rapidly improving symptoms at the discretion of the investigators；
4. NIHSS consciousness score 1a>2, or epileptic seizure, hemiplegia after seizures or combined with other nervous/mental illness not able to cooperate or unwilling to cooperate；
5. Persistent blood pressure elevation (systolic > 185 mmHg or diastolic >110 mmHg), despite blood pressure lowering treatment；
6. Blood glucose < 2.8 or > 22.2 mmol/L (point of care glucose testing is acceptable)；
7. Active internal bleeding or at high risk of bleeding, e.g.: Major surgery, trauma or gastrointestinal or urinary tract haemorrhage within the previous 21 days, or arterial puncture at a non-compressible site within the previous 7 days；
8. Any known impairment in coagulation, e.g.: If on vitamin K antagonists, then INR >1.7 or prothrombin time >15 seconds; if use of any direct thrombin inhibitors or new oral anticoagulants (NOACs) during the last 48 hours unless reversal of effect can be achieved with idarucizumab; values in sensitivity laboratory tests exceed the upper limit of normal [including activated partial thromboplastin time (APTT), international normalized ratio (INR), platelet count, thrombin time (TT), or appropriate factor Xa activity assays, etc.]; if on heparin during the last 24 hours or with an elevated aPTT greater than the upper limit of normal；
9. Known defect of platelet function or platelet count below 100*109/L (patients on antiplatelet agents can be included)；
10. Ischemic stroke or myocardial infarction in previous 3 months, previous intracranial hemorrhage, severe traumatic brain injury, intracranial or intraspinal operation in previous 3 months, or known intracranial neoplasm (excluding neuroectodermal tumors such as meningioma), arteriovenous malformation or giant aneurysm；
11. Patients who would not be expected to survive more than 1 year；
12. Unable to perform CTP or MRP；
13. Large infarct on non-contrast CT brain or MRI (infarct size >1/3 MCA territory)；
14. Acute or past intracerebral hemorrhage (ICH) identified by CT or MRI, including cerebral parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid haemorrhage, and subdural / extradural hematoma；
15. Multiple arterial occlusions (bilateral MCA occlusion, MCA occlusion accompanied by basilar artery occlusion)；
16. Pregnant women, nursing mothers, or reluctant to take contraceptive measures during the trial period；
17. Unlikely to adhere to the trial protocol or follow-up；
18. Any condition that, in the investigator's judgment, could pose a hazard to the patient if study therapy is initiated or could impact the patient's ability to participate in the study；
19. Participation in any 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: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Direct EVT; During the study period, NMPA-approved stents are permitted. EVT included thrombectomy with stent retrievers, thromboaspiration, intraarterial thrombolysis, balloon angioplasty, stenting, or a combination of these approaches at the discretion of the interventional team.	Device: direct EVT; During the study period, NMPA-approved stents are permitted. EVT included thrombectomy with stent retrievers, thromboaspiration, intraarterial thrombolysis, balloon angioplasty, stenting, or a combination of these approaches at the discretion of the interventional team.
Experimental: IVT with Tenecteplase+EVT; Tenecteplase 0.25mg/kg: 1-2 vials (1.0×107 IU/16 mg per vial) Each vial of Tenecteplase is reconstituted with 3 ml sterile water for injection and adjusted to a concentration of 5.33 mg/ml. The total amount of drug will be calculated according to the subject's actual body weight and the required drug volume will be measured. The maximum dose should not exceed 25mg. Tenecteplase should be given as a single, intravenous bolus (drug administered over 5-10 seconds). Endovascular treatment (EVT) should be performed as soon as possible after Tenecteplase administration.	Drug: Tenecteplase; Tenecteplase (0.25 mg/kg, maximum dose 25mg) is given as a single, intravenous bolus (injection over 5 to 10 seconds) immediately upon randomization. EVT should be performed as soon as possible after Tenecteplase administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The modified Rankin Scale (mRS) score 0 to 2 at 90 days	The proportion of the modified Rankin Scale (mRS) score 0 to 2 at 90 days. Scores on the mRS range from 0 to 6, with higher scores indicating greater disability.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Good reperfusion at 24h after randomization	Good reperfusion at 24h after randomization (Tmax>6s improved by 90% compared with before)	24 hours
Ordinal shift analysis of mRS at 90 days (not combined mRS 5 and 6)	Ordinal shift analysis of mRS at 90 days (not combined mRS 5 and 6). Scores on the mRS range from 0 to 6, with higher scores indicating greater disability.	90 days
mRS 0-1 at 90 days	The proportion of mRS score 0 - 1 at 90 days. Scores on the mRS range from 0 to 6, with higher scores indicating greater disability.	90 days
mRS 0-3 at 90 days	The proportion of mRS 0 - 3 at 90 days. Scores on the mRS range from 0 to 6, with higher scores indicating greater disability.	90 days
mRS 5-6 at 90 days	The proportion of mRS 5 - 6 at 90 days. Scores on the mRS range from 0 to 6, with higher scores indicating greater disability.	90 days
NIHSS≤1 or a decrease of 8 points or more from baseline at 72h after randomization	NIHSS≤1 or a decrease of 8 points or more from baseline at 72h after randomization. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating a greater deficit.	72 hours
Change in stroke severity (NIHSS score) at 7 days after randomization from baseline	Change in stroke severity (NIHSS score) at 7 days after randomization from baseline. Scores on the NIHSS range from 0 to 42, with higher scores indicating a greater deficit.	7 days
Successful reperfusion prior to endovascular treatment by DSA (eTICI 2b50-3)	Successful reperfusion prior to endovascular treatment by DSA (expanded Treatment in Cerebral Infarction[eTICI] 2b50-3)	0 hours (at treatment time)
Complete recanalization according to CTA or MRA performed 24 hours after randomization	Complete recanalization according to CTA or MRA performed 24 hours after randomization (arterial occlusive lesion score [AoL]; scale range, 0 [no recanalization] to 3 [complete recanalization]).	24 hours

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Collaborators: Linyi People's Hospital
• Investigators: Principal Investigator: Fengyuan Che, MD, Linyi People's Hospital; Principal Investigator: Yunyun Xiong, MD, Beijing Tiantan Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2024
• Primary Completion (Actual): October 13, 2025
• Study Completion (Actual): October 13, 2025

Study Registration Dates

• First Submitted: January 15, 2024
• First Submitted That Met QC Criteria: January 15, 2024
• First Posted (Actual): January 24, 2024

Study Record Updates

• Last Update Posted (Actual): November 26, 2025
• Last Update Submitted That Met QC Criteria: November 21, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Thrombolysis; Tenecteplase; Endovascular Treatment; Middle cerebral artery occlusion
• 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; Infarction; Necrosis; Ischemia; Intracranial Arterial Diseases; Stroke; Cerebral Arterial Diseases; Cerebral Infarction; Pathological Conditions, Signs and Symptoms; Ischemic Stroke; Infarction, Middle Cerebral Artery; Amino Acids, Peptides, and Proteins; Proteins; Hydrolases; Enzymes; Enzymes and Coenzymes; Blood Proteins; Endopeptidases; Peptide Hydrolases; Serine Endopeptidases; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Tissue Plasminogen Activator; Tenecteplase
• Other Study ID Numbers: CSA2023YJ003

Drug and device information, study documents

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