A Phase III, prospective, double-blind, randomized, placebo-controlled trial of thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase (TIMELESS): Rationale and design

被引：22

作者：

Albers, Gregory W. ^{[1
]}

Campbell, Bruce C., V ^{[2
]}

Lansberg, Maarten G. ^{[1
]}

Broderick, Joseph ^{[3
]}

Butcher, Ken ^{[4
]}

Froehler, Michael T. ^{[5
]}

Schwamm, Lee H. ^{[6
]}

Nouh, Amre M. ^{[7
]}

Liebeskind, David S. ^{[8
]}

Toy, Florence ^{[9
]}

Yang, Ming ^{[9
]}

Massaro, Lori ^{[9
]}

Schoeffler, Megan ^{[9
]}

Purdon, Barbara ^{[9
]}

机构：

[1] Stanford Univ, Palo Alto, CA 94304 USA

[2] Univ Melbourne, Melbourne Brain Ctr, Dept Med & Neurol, Royal Melbourne Hosp, Parkville, Vic, Australia

[3] Univ Cincinnati, Cincinnati, OH USA

[4] Univ New South Wales, Sydney, NSW, Australia

[5] Vanderbilt Univ, Med Ctr, Nashville, TN USA

[6] Massachusetts Gen Hosp, Boston, MA 02114 USA

[7] Hartford HealthCare, Hartford, CT USA

[8] UCLA, Comprehens Stroke Ctr, Los Angeles, CA USA

[9] Genentech Inc, 350 DNA Way 4th Floor, San Francisco, CA 94080 USA

来源：

INTERNATIONAL JOURNAL OF STROKE | 2023年 / 18卷 / 02期

关键词：

Acute ischemic stroke; protocols; tenecteplase; thrombolysis; TIMELESS; ISCHEMIC-STROKE; THROMBECTOMY; ALTEPLASE;

D O I：

10.1177/17474930221088400

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Rationale: While thrombolysis is standard of care for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset, the benefit of tenecteplase beyond this time window is less certain. Aim: The TIMELESS trial (NCT03785678) aims to determine if treatment with tenecteplase increases the proportion of good clinical outcomes among patients with stroke due to a large vessel occlusion who present beyond 4.5 h after symptom onset. Sample size estimates: A total of 456 patients will provide > 90% power to detect differences in the distribution of modified Rankin Scale scores at Day 90 at the two-sided 0.049 significance level. Methods and design: TIMELESS is a Phase III, double-blind, randomized, placebo-controlled trial of tenecteplase with or without endovascular thrombectomy in patients with AIS and evidence of salvageable tissue via imaging who present within the 4.5- to 24-h time window with an internal carotid artery (ICA) or middle cerebral artery (MCA) (M1/M2) occlusion. Study outcomes: The primary efficacy objective of tenecteplase compared with placebo will be evaluated with ordinal modified Rankin Scale scores at Day 90. Safety will be evaluated via incidence of symptomatic intracranial hemorrhage, incidence and severity of adverse events, and mortality rate. Discussion: Results from TIMELESS will contribute to understanding of the safety and efficacy of tenecteplase administered 4.5-24 h following symptom onset for patients with an ICA or MCA occlusion.

引用

页码：237 / 241

页数：5

共 14 条

[1] Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging [J].

Albers, G. W. ;

Marks, M. P. ;

Kemp, S. ;

Christensen, S. ;

Tsai, J. P. ;

Ortega-Gutierrez, S. ;

McTaggart, R. A. ;

Torbey, M. T. ;

Kim-Tenser, M. ;

Leslie-Mazwi, T. ;

Sarraj, A. ;

Kasner, S. E. ;

Ansari, S. A. ;

Yeatts, S. D. ;

Hamilton, S. ;

Mlynash, M. ;

Heit, J. J. ;

Zaharchuk, G. ;

Kim, S. ;

Carrozzella, J. ;

Palesch, Y. Y. ;

Demchuk, A. M. ;

Bammer, R. ;

Lavori, P. W. ;

Broderick, J. P. ;

Lansberg, M. G. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (08) :708-718

[2]

American Heart Association, 2019, TARG STROK PHAS 3

[3] Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke [J].

Campbell, B. C. V. ;

Mitchell, P. J. ;

Churilov, L. ;

Yassi, N. ;

Kleinig, T. J. ;

Dowling, R. J. ;

Yan, B. ;

Bush, S. J. ;

Dewey, H. M. ;

Thijs, V. ;

Scroop, R. ;

Simpson, M. ;

Brooks, M. ;

Asadi, H. ;

Wu, T. Y. ;

Shah, D. G. ;

Wijeratne, T. ;

Ang, T. ;

Miteff, F. ;

Levi, C. R. ;

Rodrigues, E. ;

Zhao, H. ;

Salvaris, P. ;

Garcia-Esperon, C. ;

Bailey, P. ;

Rice, H. ;

de Villiers, L. ;

Brown, H. ;

Redmond, K. ;

Leggett, D. ;

Fink, J. N. ;

Collecutt, W. ;

Wong, A. A. ;

Muller, C. ;

Coulthard, A. ;

Mitchell, K. ;

Clouston, J. ;

Mahady, K. ;

Field, D. ;

Ma, H. ;

Phan, T. G. ;

Chong, W. ;

Chandra, R. V. ;

Slater, L. -A. ;

Krause, M. ;

Harrington, T. J. ;

Faulder, K. C. ;

Steinfort, B. S. ;

Bladin, C. F. ;

Sharma, G. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (17) :1573-1582

[4] 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 [J].

Campbell, Bruce C. V. ;

Mitchell, Peter J. ;

Churilov, Leonid ;

Yassi, Nawaf ;

Kleinig, Timothy J. ;

Dowling, Richard J. ;

Yan, Bernard ;

Bush, Steven J. ;

Thijs, Vincent ;

Scroop, Rebecca ;

Simpson, Marion ;

Brooks, Mark ;

Asadi, Hamed ;

Wu, Teddy Y. ;

Shah, Darshan G. ;

Wijeratne, Tissa ;

Zhao, Henry ;

Alemseged, Fana ;

Ng, Felix ;

Bailey, Peter ;

Rice, Henry ;

de Villiers, Laetitia ;

Dewey, Helen M. ;

Choi, Philip M. C. ;

Brown, Helen ;

Redmond, Kendal ;

Leggett, David ;

Fink, John N. ;

Collecutt, Wayne ;

Kraemer, Thomas ;

Krause, Martin ;

Cordato, Dennis ;

Field, Deborah ;

Ma, Henry ;

O'Brien, Bill ;

Clissold, Benjamin ;

Miteff, Ferdinand ;

Clissold, Anna ;

Cloud, Geoffrey C. ;

Bolitho, Leslie E. ;

Bonavia, Luke ;

Bhattacharya, Arup ;

Wright, Alistair ;

Mamun, Abul ;

O'Rourke, Fintan ;

Worthington, John ;

Wong, Andrew A. ;

Levi, Christopher R. ;

Bladin, Christopher F. ;

Sharma, Gagan .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2020, 323 (13) :1257-1265

[5] Extending thrombolysis to 4.5-9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data [J].

Campbell, Bruce C., V ;

Ma, Henry ;

Ringleb, Peter A. ;

Parsons, Mark W. ;

Churilov, Leonid ;

Bendszus, Martin ;

Levi, Christopher R. ;

Hsu, Chung ;

Kleinig, Timothy J. ;

Fatar, Marc ;

Leys, Didier ;

Molina, Carlos ;

Wijeratne, Tissa ;

Curtze, Sami ;

Dewey, Helen M. ;

Barber, P. Alan ;

Butcher, Kenneth S. ;

De Silva, Deidre A. ;

Bladin, Christopher F. ;

Yassi, Nawaf ;

Pfaff, Johannes A. R. ;

Sharma, Gagan ;

Bivard, Andrew ;

Desmond, Patricia M. ;

Schwab, Stefan ;

Schellinger, Peter D. ;

Yan, Bernard ;

Mitchell, Peter J. ;

Serena, Joaquin ;

Toni, Danilo ;

Thijs, Vincent ;

Hacke, Werner ;

Davis, Stephen M. ;

Donnan, Geoffrey A. .

LANCET, 2019, 394 (10193) :139-147

[6] 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 [J].

Emberson, Jonathan ;

Lees, Kennedy R. ;

Lyden, Patrick ;

Blackwell, Lisa ;

Albers, Gregory ;

Bluhmki, Erich ;

Brott, Thomas ;

Cohen, Geoff ;

Davis, Stephen ;

Donnan, Geoffrey ;

Grotta, James ;

Howard, George ;

Kaste, Markku ;

Koga, Masatoshi ;

von Kummer, Ruediger ;

Lansberg, Maarten ;

Lindley, Richard I. ;

Murray, Gordon ;

Olivot, Jean Marc ;

Parsons, Mark ;

Tilley, Barbara ;

Toni, Danilo ;

Toyoda, Kazunori ;

Wahlgren, Nils ;

Wardlaw, Joanna ;

Whiteley, William ;

del Zoppo, Gregory J. ;

Baigent, Colin ;

Sandercock, Peter ;

Hacke, Werner .

LANCET, 2014, 384 (9958) :1929-1935

[7] Alteplase versus tenecteplase for thrombolysis after Cross Mark ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study [J].

Huang, Xuya ;

Cheripelli, Bharath Kumar ;

Lloyd, Suzanne M. ;

Kalladka, Dheeraj ;

Moreton, Fiona Catherine ;

Siddiqui, Aslam ;

Ford, Ian ;

Muir, Keith W. .

LANCET NEUROLOGY, 2015, 14 (04) :368-376

[8] Penumbral Imaging-Based Thrombolysis with Tenecteplase Is Feasible up to 24 Hours after Symptom Onset [J].

Kate, Mahesh ;

Wannamaker, Robert ;

Kamble, Harsha ;

Riaz, Parnian ;

Gioia, Laura C. ;

Buck, Brian ;

Jeerakathil, Thomas ;

Smyth, Penelope ;

Shuaib, Ashfaq ;

Butcher, Kenneth ;

Emery, Derek .

JOURNAL OF STROKE, 2018, 20 (01) :122-130

[9] Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct [J].

Nogueira, R. G. ;

Jadhav, A. P. ;

Haussen, D. C. ;

Bonafe, A. ;

Budzik, R. F. ;

Bhuva, P. ;

Yavagal, D. R. ;

Ribo, M. ;

Cognard, C. ;

Hanel, R. A. ;

Sila, C. A. ;

Hassan, A. E. ;

Millan, M. ;

Levy, E. I. ;

Mitchell, P. ;

Chen, M. ;

English, J. D. ;

Shah, Q. A. ;

Silver, F. L. ;

Pereira, V. M. ;

Mehta, B. P. ;

Baxter, B. W. ;

Abraham, M. G. ;

Cardona, P. ;

Veznedaroglu, E. ;

Hellinger, F. R. ;

Feng, L. ;

Kirmani, J. F. ;

Lopes, D. K. ;

Jankowitz, B. T. ;

Frankel, M. R. ;

Costalat, V. ;

Vora, N. A. ;

Yoo, A. J. ;

Malik, A. M. ;

Furlan, A. J. ;

Rubiera, M. ;

Aghaebrahim, A. ;

Olivot, J. -M. ;

Tekle, W. G. ;

Shields, R. ;

Graves, T. ;

Lewis, R. J. ;

Smith, W. S. ;

Liebeskind, D. S. ;

Saver, J. L. ;

Jovin, T. G. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (01) :11-21

[10] A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke [J].

Parsons, Mark ;

Spratt, Neil ;

Bivard, Andrew ;

Campbell, Bruce ;

Chung, Kong ;

Miteff, Ferdinand ;

O'Brien, Bill ;

Bladin, Christopher ;

McElduff, Patrick ;

Allen, Chris ;

Bateman, Grant ;

Donnan, Geoffrey ;

Davis, Stephen ;

Levi, Christopher .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (12) :1099-1107

← 1 2 →