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, Open-label, Blinded Endpoint (PROBE), Phase 3, Randomized Controlled 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 M2 occlusion.

Study Overview

• Status: Active, not recruiting
• Conditions: Thrombolysis; Ischemic Stroke, Acute; Endovascular Treatment
• Intervention / Treatment: Drug: rhTNK-tPA; Device: direct EVT

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 rhTNK-tPA (0.25mg/kg, maximum 25mg) or without preceding intravenous rhTNK-tPA in a 1:1 ratio. Written informed consent will be needed.

• Study Type: Interventional
• Enrollment (Estimated): 390
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100070
      • Beijing Tiantan Hospital, Capital Medical University
  • Jiangsu
    • Nanjing, Jiangsu, China, 210002
      • Eastern Theater General Hospital
  • Shaanxi
    • Xi'an, Shaanxi, China, 710061
      • First Affiliated Hospital of Xi 'an Jiaotong University
  • Shandong
    • Heze, Shandong, China, 274400
      • Heze Municipal Hospital
    • Liaocheng, Shandong, China, 252006
      • Liaocheng Third People's Hospital
    • Linyi, Shandong, China, 276003
      • Linyi People's 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
  • Shanxi
    • Linfen, Shanxi, China, 637699
      • Linfen Central 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 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 + perfusion weighted imaging (PWI) (analyzed by perfusion analysis software with Class II and above medical device certificates) [ischemic core volume (defined as CBF<30%) <70mL, mismatch ratio≥1.8, mismatch volume≥15mL].
5. Pre-stroke 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 Recombinant Human TNK Tissue-type Plasminogen Activator for Injection (rhTNK-tPA).
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 (on random glucose testing is acceptable).
7. Active internal bleeding or at high risk of bleeding, e.g.: Major surgery, trauma or gastrointestinal or urinary tract hemorrhage 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 (neuroectodermal tumor excluded like 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 PWI.
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 hemorrhage, 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
Experimental: IVT with rhTNK-tPA+EVT; rhTNK-tPA 0.25mg/kg: 1-2 vials (1.0×107 IU/16 mg per vial) Each vial of rhTNK-tPA 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. rhTNK-tPA 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 rhTNK-tPA administration.	Drug: rhTNK-tPA; rhTNK-tPA (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 rhTNK-tPA administration.; Other Names: Tenecteplase
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The modified Rankin Scale score (mRS) 0 to 2 at 90 days	The proportion of the modified Rankin Scale score (mRS) 0 to 2 at 90 days	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mRS at 90 days (shift analysis)	Ordinal distribution of mRS at 90 days	90 days
mRS 0-1 at 90 days	The proportion of mRS 0 - 1 at 90 days	90 days
mRS 0-3 at 90 days	The proportion of mRS 0 - 3 at 90 days	90 days
mRS 5-6 at 90 days	The proportion of mRS 5 - 6 at 90 days	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	72 hours
Change of stroke severity at 7 days after randomization from baseline	Change of stroke severity (NIHSS score) at 7 days after randomization from baseline	7 days
Successful recanalization prior to EVT by DSA	Successful recanalization prior to EVT by DSA (defined as eTICI score of 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 (AoL recanalization score)	24 hours
Good reperfusion at 24h after randomization	Good reperfusion at 24h after randomization (Tmax>6s improved by 90% compared with before)	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): December 16, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Thrombolysis; Tenecteplase; Endovascular Treatment; Middle cerebral artery occlusion
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Infarction, Middle Cerebral Artery; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; 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