Tenecteplase or Reteplase as Bridging Thrombolysis Before Thrombectomy in Acute Ischemic Cerebrovascular Events

Official title

Tenecteplase or Reteplase as Bridging Thrombolysis Before Thrombectomy in Acute Ischemic Cerebrovascular Events (TRACE-BRIDGE): A Multicenter, Randomized, Open-Label, Three-Arm, Blinded-Endpoint Phase III Trial

Overview

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

• Drug rhTNK-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.
• Drug Reteplase 10 Units (U) plus a second dose of reteplase 10 U
  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 E
• Procedure No thrombolysis (thrombectomy alone)
  Patients will undergo mechanical thrombectomy according to standard practice, without administration of intravenous thrombolytic agents.

Primary outcome measures

• Functional Independence [Time frame: From randomization to 90 days after randomization (±7 days), with outcome assessment performed by blinded assessors.]

Secondary outcome measures (12)

• Excellent functional outcome [Time frame: From randomization to 90 days after randomization (±7 days), with outcome assessment performed by blinded assessors.]
• Favorable functional outcome [Time frame: 90 days after randomization (±7 days), assessed by blinded outcome assessors.]
• Early neurological improvement [Time frame: 22-36 hours after randomization]
• Neurological improvement [Time frame: Day 7 after randomization or discharge, whichever occurs first (±1 day)]
• Pre-procedural recanalization [Time frame: During the endovascular procedure, before endovascular device manipulation]
• Near-complete reperfusion post endovascular treatment [Time frame: At the end of the endovascular procedure (immediately after completion of the procedure)]
• Successful reperfusion post endovascular Treatment [Time frame: At the end of the endovascular procedure (immediately after completion of the procedure)]
• First-pass reperfusion [Time frame: Immediately after the first thrombectomy pass during the endovascular procedure]
• Modified first-pass reperfusion [Time frame: Immediately after the first thrombectomy pass during the endovascular procedure]
• Health Related Quality of Life [Time frame: 90 days after randomization (±7 days)]
• Barthel index≥95 [Time frame: 90 days after randomization (±7 days)]
• Symptomatic intracranial hemorrhage [Time frame: Up to 36 hours from randomization]

Eligibility criteria

Inclusion criteria

• 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.
• 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
• Age ⩾ 18 years at the time of signing the informed consent form
• ASPECTS 6-10
• Informed consent from the patients or their legal representative.

Exclusion criteria

• Intracranial hemorrhage (ICH) identified by CT or MRI
• Rapidly improving symptoms at the discretion of the investigator
• mRS > 2 before stroke onset.
• Massive cerebral infarction (infarct size greater than one-third of the blood middle cerebral artery supply area) suggested by CT.
• Known contraindication to imaging with contrast agents
• Planned adjunct intra-arterial (IA) thrombolysis during or after endovascular treatment (EVT).
• Secondary transfer from a primary stroke center
• Any terminal illness such that patient would not be expected to survive more than one year
• 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
• Pregnant women

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 5 centers

• Beijing Tiantan Hospital, Capital Medical Universiity — Beijing
• Zhongnan Hospital of Wuhan University — Wuhan
• Xiangtan Central Hospital — Xiangtan
• Rizhao Hospital of Traditional Chinese Medicine — Rizhao
• Ya'an People's Hospital — Ya'an

Publications

• Fischer U, Kaesmacher J, Strbian D, Eker O, Cognard C, Plattner PS, Butikofer L, Mordasini P, Deppeler S, Pereira VM, Albucher JF, Darcourt J, Bourcier R, Benoit G, Papagiannaki C, Ozkul-Wermester O, Sibolt G, Tiainen M, Gory B, Richard S, Liman J, Ernst MS, Boulanger M, Barbier C, Mechtouff L, Zhang L, Marnat G, Sibon I, Nikoubashman O, Reich A, Consoli A, Lapergue B, Ribo M, Tomasello A, Saleme PMID 35810756
• LeCouffe NE, Kappelhof M, Treurniet KM, Rinkel LA, Bruggeman AE, Berkhemer OA, Wolff L, van Voorst H, Tolhuisen ML, Dippel DWJ, van der Lugt A, van Es ACGM, Boiten J, Lycklama A Nijeholt GJ, Keizer K, Gons RAR, Yo LSF, van Oostenbrugge RJ, van Zwam WH, Roozenbeek B, van der Worp HB, Lo RTH, van den Wijngaard IR, de Ridder IR, Costalat V, Arquizan C, Lemmens R, Demeestere J, Hofmeijer J, Martens JM PMID 34758251
• Zi W, Qiu Z, Li F, Sang H, Wu D, Luo W, Liu S, Yuan J, Song J, Shi Z, Huang W, Zhang M, Liu W, Guo Z, Qiu T, Shi Q, Zhou P, Wang L, Fu X, Liu S, Yang S, Zhang S, Zhou Z, Huang X, Wang Y, Luo J, Bai Y, Zhang M, Wu Y, Zeng G, Wan Y, Wen C, Wen H, Ling W, Chen Z, Peng M, Ai Z, Guo F, Li H, Guo J, Guan H, Wang Z, Liu Y, Pu J, Wang Z, Liu H, Chen L, Huang J, Yang G, Gong Z, Shuai J, Nogueira RG, Yang Q PMID 33464335
• Suzuki K, Matsumaru Y, Takeuchi M, Morimoto M, Kanazawa R, Takayama Y, Kamiya Y, Shigeta K, Okubo S, Hayakawa M, Ishii N, Koguchi Y, Takigawa T, Inoue M, Naito H, Ota T, Hirano T, Kato N, Ueda T, Iguchi Y, Akaji K, Tsuruta W, Miki K, Fujimoto S, Higashida T, Iwasaki M, Aoki J, Nishiyama Y, Otsuka T, Kimura K; SKIP Study Investigators. Effect of Mechanical Thrombectomy Without vs With Intravenous T PMID 33464334
• Mitchell PJ, Yan B, Churilov L, Dowling RJ, Bush SJ, Bivard A, Huo XC, Wang G, Zhang SY, Ton MD, Cordato DJ, Kleinig TJ, Ma H, Chandra RV, Brown H, Campbell BCV, Cheung AK, Steinfort B, Scroop R, Redmond K, Miteff F, Liu Y, Duc DP, Rice H, Parsons MW, Wu TY, Nguyen HT, Donnan GA, Miao ZR, Davis SM; DIRECT-SAFE Investigators. Endovascular thrombectomy versus standard bridging thrombolytic with endo PMID 35810757
• Majoie CB, Cavalcante F, Gralla J, Yang P, Kaesmacher J, Treurniet KM, Kappelhof M, Yan B, Suzuki K, Zhang Y, Li F, Morimoto M, Zhang L, Miao Z, Rinkel LA, Huang J, Otsuka T, Wang S, Davis S, Cognard C, Hong B, Coutinho JM, Song J, Chen W, Emmer BJ, Eker O, Zhang L, Dobrocky T, Nguyen HT, Bush S, Peng Y, LeCouffe NE, Takeuchi M, Han H, Matsumaru Y, Strbian D, Lingsma HF, Nieboer D, Yang Q, Meinel PMID 37640037
• Wang Y, Li S, Pan Y, Li H, Parsons MW, Campbell BCV, Schwamm LH, Fisher M, Che F, Dai H, Li D, Li R, Wang J, Wang Y, Zhao X, Li Z, Zheng H, Xiong Y, Meng X; TRACE-2 Investigators. Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial. Lancet. 2023 Feb 25;401(10377):645-654. doi: 10.1016/S0 PMID 36774935
• Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Dewey HM, Thijs V, Scroop R, Simpson M, Brooks M, Asadi H, Wu TY, Shah DG, Wijeratne T, Ang T, Miteff F, Levi CR, Rodrigues E, Zhao H, Salvaris P, Garcia-Esperon C, Bailey P, Rice H, de Villiers L, Brown H, Redmond K, Leggett D, Fink JN, Collecutt W, Wong AA, Muller C, Coulthard A, Mitchell K, Clouston J, Mahad PMID 29694815

Identifiers

NCT: NCT07748039 · TRACEBRIDGE-2026-03 · 2025-A02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗