Acute Ischemic Stroke, Anterior Circulation Brain Infarction, Large Vessel Occlusion
Conditions
Keywords
acute ischemic stroke, thrombolysis, thrombectomy, tenecteplase, reteplase
Brief summary
Acute ischemic stroke caused by large vessel occlusion (LVO) is a major cause of disability, and mechanical thrombectomy (MT) has become the standard treatment for eligible patients. However, the optimal role of intravenous thrombolysis before MT remains uncertain. The TRACE-BRIDGE trial is a phase 3, investigator-initiated, multicenter, randomized, open-label trial with blinded outcome assessment (PROBE design) evaluating different bridging thrombolysis strategies before MT. The trial will enroll adults with acute ischemic stroke presenting within 4.5 hours of symptom onset and with imaging-confirmed anterior circulation LVO who are eligible for intravenous thrombolysis and MT. Participants will be randomly assigned in a 1:1:1 ratio to receive tenecteplase plus MT, reteplase plus MT, or direct MT alone. The TRACE-BRIDGE trial aims to evaluate the efficacy and safety of bridging thrombolysis with tenecteplase or reteplase before mechanical thrombectomy compared with direct mechanical thrombectomy. The primary outcome is functional independence, defined as a modified Rankin Scale score of 0-2 at 90 days after randomization. If superiority of bridging thrombolysis is demonstrated, the trial will further evaluate whether reteplase is non-inferior to tenecteplase as a bridging thrombolytic strategy.
Detailed description
Mechanical thrombectomy (MT) has become the standard of care for eligible patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). Randomized controlled trials and individual patient-level meta-analyses have demonstrated substantial improvements in functional outcomes with MT compared with medical management alone. However, the optimal strategy for intravenous thrombolysis before mechanical thrombectomy remains uncertain. Previous randomized trials evaluating bridging thrombolysis have primarily investigated alteplase, and the additional clinical benefit of intravenous thrombolysis before MT compared with direct MT has not been conclusively established. Tenecteplase and reteplase are two thrombolytic agents that may provide potential alternatives to alteplase in the bridging thrombolysis setting. Tenecteplase, administered at a dose of 0.25 mg/kg, has demonstrated promising efficacy and safety profiles in patients with acute ischemic stroke, with increasing evidence supporting its use as a bridging thrombolytic agent before MT. Reteplase, administered as two intravenous bolus doses of 18 mg, has also shown potential as an alternative thrombolytic agent and requires further evaluation in patients undergoing MT. The TRACE-BRIDGE trial is a phase 3, investigator-initiated, multicenter, randomized, open-label trial with blinded outcome assessment (PROBE design). The trial will enroll adults with acute ischemic stroke who present within 4.5 hours of symptom onset and have imaging-confirmed anterior circulation large vessel occlusion. Participants must meet predefined eligibility criteria for intravenous thrombolysis and mechanical thrombectomy. Eligible participants will be randomly assigned in a 1:1:1 ratio to receive tenecteplase plus MT, reteplase plus MT, or direct MT alone. The primary outcome is functional independence, defined as a modified Rankin Scale score of 0-2 at 90 days after randomization. The primary objective of the trial is to determine whether bridging thrombolysis with tenecteplase or reteplase, analyzed as a combined treatment strategy, is superior to direct mechanical thrombectomy alone in achieving functional independence at 90 days. If superiority is established, the trial will further evaluate whether reteplase is non-inferior to tenecteplase as a bridging thrombolytic strategy. The planned sample size is 1,440 participants, with a maximum total sample size of 1,800 participants if sample size re-estimation is performed according to pre-specified criteria. An interim analysis is planned after approximately 60% of the originally planned sample size has been enrolled. The interim analysis will include a non-binding futility assessment and may include sample size re-estimation.
Interventions
DRUGrhTNK-tPA (0.25mg/kg)
Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) administered as a single intravenous bolus at a dose of 0.25 mg/kg (maximum dose 25 mg) within 4.5 hours of symptom onset prior to mechanical thrombectomy.
Two intravenous bolus injections of 18 mg each, administered within 4.5 hours of onset over approximately 2 minutes per bolus, separated by a 30-minute interval prior to thrombectomy. To avoid delays in reperfusion therapy, groin puncture and MT procedures may be initiated after administration of the first 18 mg bolus, without waiting for completion of the second bolus. Unless contraindicated, the second rPA bolus should be administered according to the scheduled dosing regimen irrespective of EVT status.
PROCEDURENo thrombolysis (thrombectomy alone)
Patients will undergo mechanical thrombectomy according to standard practice, without administration of intravenous thrombolytic agents.
Sponsors
Yongjun Wang
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
This trial is a Phase 3, investigator-initiated, Multicenter, Three-armed, Open-Label with Blinded Outcome Assessment (PROBE) Randomized Trial. All outcome measures will be assessed by investigators blinded to treatment allocation.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with acute ischemic stroke presenting within 4.5 hours of symptom onset who are eligible for intravenous thrombolytic therapy. A baseline non-contrast CT or MRI is required for screening. 2. Large vessel occlusion on computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) of the intracranial carotid artery (ICA) or middle cerebral artery (MCA) M1 3. Age ⩾ 18 years at the time of signing the informed consent form 4. ASPECTS 6-10 5. Informed consent from the patients or their legal representative.
Exclusion criteria
1. Intracranial hemorrhage (ICH) identified by CT or MRI 2. Rapidly improving symptoms at the discretion of the investigator 3. mRS \> 2 before stroke onset. 4. Massive cerebral infarction (infarct size greater than one-third of the blood middle cerebral artery supply area) suggested by CT. 5. Known contraindication to imaging with contrast agents 6. Planned adjunct intra-arterial (IA) thrombolysis during or after endovascular treatment (EVT). 7. Secondary transfer from a primary stroke center 8. Any terminal illness such that patient would not be expected to survive more than one year 9. 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 10. Pregnant women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional Independence | From randomization to 90 days after randomization (±7 days), with outcome assessment performed by blinded assessors. | Proportion of participants achieving functional independence, defined as a modified Rankin Scale (mRS) score of 0-2 at 90 days after randomization. The mRS ranges from 0 (no symptoms) to 6 (death), with higher scores indicating greater disability. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Excellent functional outcome | From randomization to 90 days after randomization (±7 days), with outcome assessment performed by blinded assessors. | Proportion of participants achieving an excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0-1 at 90 days after randomization. The mRS ranges from 0 (no symptoms) to 6 (death), with higher scores indicating greater disability. |
| Favorable functional outcome | 90 days after randomization (±7 days), assessed by blinded outcome assessors. | Proportion of participants achieving a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0-3 at 90 days after randomization. The mRS ranges from 0 (no symptoms) to 6 (death), with higher scores indicating greater disability. |
| Early neurological improvement | 22-36 hours after randomization | Proportion of participants achieving major early neurological recovery at 24 hours after randomization, defined as a reduction in National Institutes of Health Stroke Scale (NIHSS) score from baseline of ≥8 points or an NIHSS score of 0-1. The NIHSS ranges from 0 (no neurological deficit) to 42 (maximum neurological impairment), with higher scores indicating greater neurological impairment. |
| Neurological improvement | Day 7 after randomization or discharge, whichever occurs first (±1 day) | Proportion of participants achieving neurological improvement at day 7 or discharge, whichever occurs first, defined as a reduction in National Institutes of Health Stroke Scale (NIHSS) score from baseline of ≥8 points or an NIHSS score of 0-1. The NIHSS ranges from 0 (no neurological deficit) to 42 (maximum neurological impairment), with higher scores indicating greater neurological impairment. |
| Pre-procedural recanalization | During the endovascular procedure, before endovascular device manipulation | Proportion of participants with successful reperfusion on initial diagnostic angiography before any endovascular device manipulation, defined as an expanded Thrombolysis in Cerebral Infarction (eTICI) grade of 2b, 2c, or 3. The eTICI grading system is an angiographic scale used to assess reperfusion after endovascular therapy, ranging from 0 (no reperfusion) to 3 (complete reperfusion), with higher grades indicating greater reperfusion. |
| Near-complete reperfusion post endovascular treatment | At the end of the endovascular procedure (immediately after completion of the procedure) | Proportion of participants achieving near-complete reperfusion at the end of the endovascular procedure, defined as an expanded Thrombolysis in Cerebral Infarction (eTICI) grade of 2c or 3. The eTICI grade of 2c or 3 indicates near-complete to complete reperfusion, with residual perfusion defects limited to slow flow in a few distal cortical vessels or small distal cortical emboli. |
| Successful reperfusion post endovascular Treatment | At the end of the endovascular procedure (immediately after completion of the procedure) | Proportion of participants achieving successful reperfusion at the end of the endovascular procedure, defined as an expanded Thrombolysis in Cerebral Infarction (eTICI) grade of 2b, 2c, or 3. The eTICI grading system is an angiographic scale used to assess reperfusion after endovascular therapy, ranging from 0 (no reperfusion) to 3 (complete reperfusion), with higher grades indicating greater reperfusion. An eTICI grade of 2b, 2c, or 3 indicates reperfusion of at least 50% of the affected vascular territory. |
| First-pass reperfusion | Immediately after the first thrombectomy pass during the endovascular procedure | Proportion of participants achieving near-complete reperfusion after the first thrombectomy pass, defined as an expanded Thrombolysis in Cerebral Infarction (eTICI) grade of 2c or 3. The eTICI grading system is an angiographic scale used to assess reperfusion after endovascular therapy, ranging from 0 (no reperfusion) to 3 (complete reperfusion), with higher grades indicating greater reperfusion. An eTICI grade of 2c or 3 represents near-complete or complete reperfusion, respectively. |
| Modified first-pass reperfusion | Immediately after the first thrombectomy pass during the endovascular procedure | Proportion of participants achieving a modified first-pass effect, defined as successful reperfusion with an expanded Thrombolysis in Cerebral Infarction (eTICI) grade of 2b, 2c, or 3 after a single thrombectomy pass. The eTICI grading system is an angiographic scale used to assess reperfusion after endovascular therapy, ranging from 0 (no reperfusion) to 3 (complete reperfusion), with higher grades indicating greater reperfusion. |
| Health Related Quality of Life | 90 days after randomization (±7 days) | Health-related quality of life assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire at 90 days after randomization. The EQ-5D-5L is a standardized instrument used to describe and value health status across five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension is rated on five levels of severity: no problems, slight problems, moderate problems, severe problems, and extreme problems. |
| Barthel index≥95 | 90 days after randomization (±7 days) | Proportion of participants achieving a Barthel Index (BI) score of ≥95 at 90 days after randomization. The BI is a standardized scale used to assess activities of daily living and functional independence, ranging from 0 (complete dependence) to 100 (complete independence), with higher scores indicating greater functional ability. |
| Symptomatic intracranial hemorrhage | Up to 36 hours from randomization | Symptomatic intracranial hemorrhage (sICH) based on modified Heidelberg Bleeding Classification intracranial hemorrhage on follow-up imaging associated with neurological deterioration (≥4-point increase in total NIHSS or ≥2-point increase in one NIHSS item), major medical intervention such as intubation, hemicraniectomy, external ventricular drainage, or death. |
| Parenchymal Hematoma Type 2 | Up to 36 hours from randomization | Proportion of participants with parenchymal hematoma type 2 (PH2), defined as a blood clot involving more than 30% of the infarcted area with substantial mass effect, according to the Heidelberg Bleeding Classification. |
| Procedure-related complications | From the start of the endovascular procedure to 7 days after randomization | Proportion of participants experiencing endovascular procedure-related complications, including vessel perforation, vessel dissection, distal embolization to a new territory (ENT), clinically significant vasospasm, access site complications, and contrast extravasation unrelated to vessel perforation. |
| Major Bleeding | 90 days after randomization (±7 days) | Proportion of participants experiencing major bleeding within 90 days after randomization, defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, including fatal bleeding, bleeding in a critical organ (e.g., intracranial, intraspinal, intraocular, or retroperitoneal bleeding), a fall in hemoglobin level of ≥2 g/dL, or transfusion of ≥2 units of red blood cells. |
| Clinically relevant non-major bleeding | 90 days after randomization (±7 days) | Proportion of participants experiencing clinically relevant non-major bleeding (CRNMB) within 90 days after randomization, defined as bleeding that does not meet criteria for major bleeding but requires medical intervention, unscheduled medical evaluation, hospitalization, or close monitoring. |
| All-cause mortality at 7 days | Within 7 days after randomization | Proportion of participants who died from any cause within 7 days after randomization. |
| All-cause mortality at 90 days | 90 days after randomization (±7 days) | Proportion of participants who died from any cause within 90 days after randomization. |
| Adverse events, serious adverse events, and suspected unexpected serious adverse reactions | 90 days after randomization (±7 days) | Proportion of participants experiencing adverse events (AEs), serious adverse events (SAEs), or suspected unexpected serious adverse reactions (SUSARs) within 90 days after randomization. |
Countries
China
Contacts
CONTACTYongjun Wang, MD
CONTACTBowei Zhang, MD
PRINCIPAL_INVESTIGATORYongjun Wang
Beijing Tiantan Hospital
Outcome results
None listed