Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-II (TRACE II): rationale and design

Shuya Li, Bruce C V Campbell, Lee H Schwamm, Marc Fisher, Mark Parsons, Hao Li, Yuesong Pan, Yongjun Wang, TRACE II investigators, Shuya Li, Bruce C V Campbell, Lee H Schwamm, Marc Fisher, Mark Parsons, Hao Li, Yuesong Pan, Yongjun Wang, TRACE II investigators

Abstract

Background and purpose: Tenecteplase (TNK) is a promising agent for treatment of acute ischaemic stroke (AIS). We hypothesised that recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) is non-inferior to rt-PA in achieving excellent functional outcome at 90 days, when administered within 4.5 hours of ischaemic stroke onset.

Methods and design: Tenecteplase Reperfusion therapy in Acute ischemic Cerebrovascular Events (TRACE) is a phase III, multicentre, prospective, randomised, open-label, blinded-end point non-inferiority study. Patients eligible for intravenous thrombolysis therapy are randomised to rhTNK-tPA 0.25 mg/kg (single bolus) to a maximum of 25 mg or rt-PA 0.9 mg/kg (10% bolus+90% infusion/1 hour) to a maximum of 90 mg. Medications considered necessary for the patient's health may be given at the discretion of the investigator during 90-day follow-up.

Study outcomes: The primary study outcome is excellent functional outcome defined as modified Rankin Scale (mRS) 0-1 at 90 days. Secondary efficacy outcomes include favourable functional outcome defined as mRS ≤2 at 90 days, ordinal distribution of mRS and major neurological improvement on the National Institutes of Health Stroke Scale. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours and death from any cause.

Discussion: There is no completed registration study of TNK in AIS worldwide. TRACE II strives to provide evidence for a new drug application for rhTNK-tPA in AIS within 4.5 hours through a well-designed and rigorously executed randomised trial in China.

Trial registration number: NCT04797013.

Keywords: stroke; thrombolysis.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

References

    1. GBD 2016 Lifetime Risk of Stroke Collaborators, Feigin VL, Nguyen G, et al. . Global, regional, and Country-Specific lifetime risks of stroke, 1990 and 2016. N Engl J Med 2018;379:2429–37. 10.1056/NEJMoa1804492
    1. Zhou M, Wang H, Zeng X, et al. . Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the global burden of disease study 2017. The Lancet 2019;394:1145–58. 10.1016/S0140-6736(19)30427-1
    1. Wang Y-J, Li Z-X, Gu H-Q, et al. . China stroke statistics 2019: a report from the National center for healthcare quality management in neurological diseases, China national clinical research center for neurological diseases, the Chinese stroke association, National center for chronic and non-communicable disease control and prevention, Chinese center for disease control and prevention and Institute for global neuroscience and stroke collaborations. Stroke Vasc Neurol 2020;5:211–39. 10.1136/svn-2020-000457
    1. Powers WJ, Rabinstein AA, Ackerson T, et al. . Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American heart Association/American stroke association. Stroke 2019;50:e344–418. 10.1161/STR.0000000000000211
    1. Emberson J, Lees KR, Lyden P, et al. . Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929–35. 10.1016/S0140-6736(14)60584-5
    1. Liu L, Chen W, Zhou H, et al. . Chinese stroke association guidelines for clinical management of cerebrovascular disorders: Executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases. Stroke Vasc Neurol 2020;5:159–76. 10.1136/svn-2020-000378
    1. Llevadot J, Giugliano RP, Antman EM. Bolus fibrinolytic therapy in acute myocardial infarction. JAMA 2001;286:442–9. 10.1001/jama.286.4.442
    1. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, Van De Werf F, Adgey J, et al. . Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716–22. 10.1016/S0140-6736(99)07403-6
    1. Wallentin L, Goldstein P, Armstrong PW, et al. . Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003;108:135–42. 10.1161/01.CIR.0000081659.72985.A8
    1. Parsons M, Spratt N, Bivard A, et al. . A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012;366:1099–107. 10.1056/NEJMoa1109842
    1. Huang X, Cheripelli BK, Lloyd SM, et al. . Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol 2015;14:368–76. 10.1016/S1474-4422(15)70017-7
    1. Campbell BC, Mitchell PJ, Churilov L, et al. . Tenecteplase versus alteplase before endovascular thrombectomy (EXTEND-IA TNK): a multicenter, randomized, controlled study. Int J Stroke 2018;13:328–34. 10.1177/1747493017733935
    1. Campbell BCV, Mitchell PJ, Churilov L, et al. . Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients with large vessel occlusion ischemic stroke: the EXTEND-IA TNK Part 2 randomized clinical trial. JAMA 2020;323:1257–65. 10.1001/jama.2020.1511
    1. Logallo N, Novotny V, Assmus J, et al. . Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol 2017;16:781–8. 10.1016/S1474-4422(17)30253-3
    1. Burgos AM, Saver JL. Evidence that tenecteplase is Noninferior to alteplase for acute ischemic stroke: meta-analysis of 5 randomized trials. Stroke 2019;50:2156–62. 10.1161/STROKEAHA.119.025080
    1. Hansson L, Hedner T, Dahlöf B. Prospective randomized open blinded end-point (probe) study. A novel design for intervention trials. Blood Press 1992;1:113–9. 10.3109/08037059209077502
    1. Berge E, Whiteley W, Audebert H, et al. . European stroke organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021;6:I–LXII. 10.1177/2396987321989865
    1. Wahlgren N, Ahmed N, Dávalos A, et al. . Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in Stroke-Monitoring study (SITS-MOST): an observational study. Lancet 2007;369:275–82. 10.1016/S0140-6736(07)60149-4
    1. Hacke W, Kaste M, Bluhmki E, et al. . Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317–29. 10.1056/NEJMoa0804656
    1. Berkowitz SD, Granger CB, Pieper KS, et al. . Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. the global utilization of streptokinase and tissue plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators. Circulation 1997;95:2508–16. 10.1161/01.cir.95.11.2508
    1. Emberson J, Lees KR, Lyden P, et al. . Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929–35. 10.1016/S0140-6736(14)60584-5
    1. Yang P, Zhang Y, Zhang L, et al. . Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med 2020;382:1981–93. 10.1056/NEJMoa2001123
    1. Nogueira RG, Tsivgoulis G. Large vessel occlusion strokes after the DIRECT-MT and SKIP trials: is the alteplase syringe half empty or half full? Stroke 2020;51:3182–6. 10.1161/STROKEAHA.120.030796
    1. Goyal M, Menon BK, van Zwam WH, et al. . Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016;387:1723–31. 10.1016/S0140-6736(16)00163-X
    1. Goyal M, Almekhlafi M, Dippel DW, et al. . Rapid alteplase administration improves functional outcomes in patients with stroke due to large vessel occlusions. Stroke 2019;50:645–51. 10.1161/STROKEAHA.118.021840
    1. Katsanos AH, Safouris A, Sarraj A, et al. . Intravenous thrombolysis with tenecteplase in patients with large vessel occlusions: systematic review and meta-analysis. Stroke 2021;52:308–12. 10.1161/STROKEAHA.120.030220
    1. Psychogios K, Palaiodimou L, Katsanos AH, et al. . Real-world comparative safety and efficacy of tenecteplase versus alteplase in acute ischemic stroke patients with large vessel occlusion. Ther Adv Neurol Disord 2021;14:1756286420986727. 10.1177/1756286420986727

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